The Oncogenic Role of Yin Yang 1

Abstract

Yin Yang 1 (YY1) is a transcription factor with diverse and complex biological functions. YY1 either activates or represses gene transcription, depending on the stimuli received by the cells and its association with other cellular factors. Since its discovery, a biological role for YY1 in tumor development and progression has been suggested because of its regulatory activities toward multiple cancer-related proteins and signaling pathways and its overexpression in most cancers. In this review, we primarily focus on YY1 studies in cancer research, including the regulation of YY1 as a transcription factor, its activities independent of its DNA binding ability, the functions of its associated proteins, and mechanisms regulating YY1 expression and activities. We also discuss the correlation of YY1 expression with clinical outcomes of cancer patients and its target potential in cancer therapy. Although there is not a complete consensus about the role of YY1 in cancers based on its activities of regulating oncogene and tumor suppressor expression, most of the currently available evidence supports a proliferative or oncogenic role of YY1 in tumorigenesis.

I. INTRODUCTION

Yin Yang 1 (YY1) (also named nuclear factor [NF] E1, delta, and upstream control region binding protein) was first discovered as a DNA binding protein by several groups in 1991 and 1992.^1–5 As a member of the GLI-Krüppel class proteins, the DNA binding domain of YY1 is located at its C-terminal zinc-finger region. YY1 is a ubiquitously expressed and evolutionarily conserved protein. Human YY1 consists of 414 amino acids and has multiple functional domains.⁶ As a transcription factor, YY1 consensus binding elements have been identified in more than 7% of vertebrate genes,⁷ suggesting its importance in modulating gene expression. Numerous studies consistently have indicated an essential role of YY1 in different biological processes, including cell growth, differentiation, and embryonic development.

The activities of YY1 in regulating gene expression were demonstrated in many early studies.^1,3–5 Depending on the compositional differences of its recruited complexes, YY1 can either repress or activate the transcription of its target genes. Among these cofactors, histone deacetylases (HDACs) and methyltransferase enhancer of zeste homolog 2 (Ezh2) suppress gene expression by promoting histone deacetylation and histone H3 lysine 27 (H3-K27) methylation, respectively, whereas histone acetyltransferases p300, cyclic adenosine monophosphate response element binding (CREB) protein (CBP), and P300/CBP-associated factor (PCAF) stimulate gene expression by acetylating histones (see reviews^6,8–10). However, several recent studies, including ours, demonstrated the DNA binding- or transcription-independent activities of YY1, which broadens the regulatory functions of YY1.¹¹

Since its discovery, nearly a thousand YY1-related articles have been published. Several previous reviews have discussed the general functions of YY1.^6,8–10 Although YY1 has a role in normal growth and development, most studies have focused on the regulatory roles of YY1 in various cancer-related signaling pathways, such as histone acetylation and methylation, and modulation of the activities or homeostasis of oncogenes and tumor suppressors. Most of these studies implicate a proliferative or promoting role of YY1 in cancer development, consistent with its overexpression status in cancers. In this review, we will focus on cancer-related studies of YY1.

The term Yin Yang is used to describe the interdependence of seemingly opposite forces in nature. The role of YY1 in tumorigenesis can also be viewed as “Yin Yang,” although its oncogenic role is clearly more prevalent than its tumor-suppressive potential, based on the available literature.

II. YIN YANG 1–REGULATED GENE EXPRESSION

When YY1 was first discovered more than 20 years ago, it was identified as a transcription factor that regulated the adeno-associated virus P5 promoter, and its overall effect depended on the viral oncogene E1A.¹ Later, Shiet al⁸ and Thomas and Seto⁶ proposed the models of YY1-regulated gene expression. YY1 controls a plethora of genes, most of which are cancer-related. The zinc-finger domain at the C-terminal of YY1 recognizes the core sequences of ACAT and CCAT in its binding elements,¹² which has been recently extended and further defined.¹³

The name Yin Yang represents its transcriptional activity in regulating gene expression. The seemingly contrary functions of YY1 depend on its recruited cofactors to target promoters, most of which are proteins that modulate the modifications of histones and DNA. The coactivators that can be recruited by YY1 include p300, CBP, PCAF, and protein arginine methyltransferase (PRMT) 4; the recruited corepressors include HDACs, Ezh2, Ezh1, and DNA methyltransferases (DNMTs). These will be discussed below in detail.

A. Yin Yang 1–Activated Gene Expression

The YY1-activated genes known to be related to cancers are listed in Table 1. When Shi et al¹ discovered the YY1 protein, its E1A-mediated “Yin Yang” effects, or gene repression and activation, on the adenovirus P5 promoter were reported. In the following studies, these seemingly contradictory effects of YY1’s transcriptional activities were observed repeatedly. In 1993, Riggs et al¹⁴ used YY1 overexpression and reporter assays to demonstrate that YY1 activated the expression of proto-oncogene c-Myc. In this study, transfected YY1 increased the levels of 2 major c-Myc messenger RNA (mRNA) transcript variants. Rezai-Zadehet al¹⁵ also showed that YY1 stimulated the c-Myc promoter and demonstrated that PRMT1-mediated methylation at the Arg3 of histone H4 (H4-R3) is important to this activation. However, 2 recent articles^17,19 showed that YY1 could regulate c-Myc expression negatively in certain scenarios. Although p300 can both stabilize c-Myc and promote c-Myc-mediated transcription,¹⁶ it also can act as a co-repressor to form a p300-HDAC3-YY1 complex that inhibits c-Myc expression.¹⁷ Ablating any of these 3 proteins results in chromatin acetylation of the c-Myc promoter and induction of c-Myc transcription. This happens when oncogene E1A is present, which disrupts the YY1-p300-HDAC3 complex and leads to regional histone acetylation on the c-Myc promoter. Consequently, the c-Myc gene is activated.¹⁸ The stimulatory effect of E1A on YY1-mediated c-Myc gene activation is depicted in Fig. 1. Another study by Hu et al¹⁹ revealed a different mechanism of YY1-mediated c-Myc activation. In Burkitt lymphoma, an immunoglobulin heavy-chain gene HS3 enhancer positively regulates c-Myc expression. YY1 binds to this HS3 enhancer and recruits CBP to this region, which increases the histone acetylation of the c-Myc promoter and activates c-Myc gene expression.

TABLE 1.

Yin Yang 1–Activated Genes and Promoters

Gene/Promoter	Function of the Gene Product	Mechanism/Observation	Reference
A. Oncogenic, proliferative and/or overexpressed genes in cancer
B23/nucleophosmin	Regulates nucleosome formation and inhibits tumor suppressors	Hepatitis C virus core, p300, and B23 itself are involved	24,25
c-Myc	Transcription factor and oncogene of various cancers	E1A converts YY1 from a repressor to an activator; p300 and HDAC3 also are involved	14,186
HER2/ERBB2/neu	Proto-oncogene in breast cancer	YY1 enhances AP-2 transcriptional activity on the human epidermal growth factor receptor 2 promoter	30,31
Cyclooxygenase-2	Oncogene of various cancers	A model with YY1 recruiting p300 and HDAC1,2 was proposed	38
c-Fos	Proto-oncogene	E1A converts YY1 from a repressor to an activator in this regulation	187
Glucose regulating protein 78/binding immunoglobulin protein	Promotes tumor proliferation, survival, metastasis, and resistance to cancer therapies	p300 and protein arginine methyltransferase 1 are recruited	34–36,188
OTX2	Oncogene of medulloblastoma	Acetylated YY1, but not the unmodified, can bind the enhancer	39,189
Snail	Enhances cell survival, movement and/ or EMT	YY1 binds a distal Snail 3′ enhancer	40,42
Msx2	EMT and tumorigenesis	Three YY1 binding sites are involved	43,190
Mitochondrial genes: Cyto C, etc.	Cell respiration	Mammalian target of rapamycin regulates YY1-PGC-1α-mediated transcription	60
DR-α	Overexpressed in cancers	YY1 directly binds to the promoter	191,192
VASAP-60/PRKCSH/80K-H	Elevated in breast cancer	Two YY1-binding sites are involved.	193
TGF-β	Overexpressed in tumor; promotes invasiveness and metastasis	A polymorphism mutation in the TGF-β promoter creates a binding site of YY1 that activates TGF-β gene	194,195
B. Tumor suppression genes
Breast cancer 1 (BRCA1)	Tumor suppressor in breast cancer	YY1 directly binds to the promoter	57
ERGIC-53	Transmembrane lectin facilitates the efficient export of a subset of secretory glycoproteins from the ER; induced by ER-stress	Activating transcription factor 6α-YY1 may associate to coactivate ERGIC-53 gene	121
HLJ1	Tumor and invasion suppressor	AP-1 and p300 may be involved	55,196
p53	Tumor suppressor	E1A and p300 can induce p53 expression further	53
p73	A member of p53 family proteins	YY1 and E2F1 cooperate p73 transcription	54
Peg3 (via conserved sequence binding element 2)	Imprinted gene with tumor suppression function	CTCF is involved in this regulation	197
RIZ1	A histone methyltransferase; altered expression in cancers; a potential tumor suppressor	Correlated with reduced H3-K9 dimethylation	198
C. Other regulatory proteins in tumorigenesis
α-SMA	Regulates pulmonary fibrosis that is associated with lung cancer	TGF-β modulates this regulation by inducing YY1 expression	147
EGFR	Cell signaling molecules involved in diverse cellular functions, including cell proliferation, differentiation, motility, and survival, and in tissue development	Sp1 and YY1 synergistically induce the epidermal growth factor receptor promoter; p53 suppresses this activation	199
GDAP1	Broadly expressed in various cancer cell lines	YY1 directly binds to the promoter	44
Histone H2a and H3	Aberrantly modified in cancers	Regulated by cell cycle	58
Histone H4	Aberrantly modified in cancers	Multiple YY1 binding sites are involved	59
Heterochromatin protein 1α (HP1α)	Reduced in invasive breast cancer cells	Two YY1 binding sites are involved	200
Line-1 (promoter)	Altered methylation in cancers	YY1 determines the correct transcription of the full-length retrotransposed product	136,201–203
MCP-2	Mediate inflammatory response	YY1 is an intermediate step of interleukin-15-regulated MCP-2 expression	204
M-opioid receptor	Cancer-related pain	Sp1 is involved	148
Myelin proteolipid protein	Primary constituent of myelin in the central nervous system	YY1 directly binds to the promoter	205
OTK18	Induced by human immunodeficiency virus infection	YY1 directly binds to the promoter	206
OX40	A therapeutic target in the treatment of autoimmunity and cancer	Sp1, Sp3, and nuclear factor κB are involved in this regulation	207,208
Poly(ADP-ribose) polymerase 1 (PARP)	Promotes poly(ADP-ribosyl)ation; related to DNA damage repair	YY1 directly binds the promoter	209
Proliferating cellular nuclear antigen (PCNA)	Involved in DNA synthesis and repair; cooperating with nucleophosmin/B23	B23 is involved; accompanied by histone H4 deacetylation	27,210
RE-1 silencing transcription factor or neuron-restrictive silencer factor	Shows both tumor suppressor and oncogenic activities	YY1 directly binds to the promoter	211,212
gp91(phox)	Catalytic subunit of the nicotinamide adenine dinucleotide phosphate oxidase; potential target of cancer therapy	Multiple YY1-interacting sites are detected	213,214
B-type natriuretic peptide	Related to patients’ response to cancer therapy	HDAC2 is recruited	215
Transferrin receptor (CD71)	Related to poor prognosis and resistant to tamoxifen in breast cancer	YY1 directly binds to the promoter	216

ADP, adenosine diphosphate; AP, activator protein; EMT, epithelial-mesenchymal transition; ER, endoplasmic reticulum; HDAC, histone deacetylase; MCP, monocyte chemotactic protein; TGF, transforming growth factor; YY1, Yin Yang 1.

FIGURE 1.

Schematic model for the stimulatory effect of E1A on Yin Yang 1 (YY1) -mediated c-Myc gene activation. YY1 forms a ternary complex with corepressors p300 and histone deacetylase (HDAC) 3, which represses c-Myc gene expression, probably in normal or resting cells. In transformed cells, the introduction of the viral oncogene E1A disrupts the YY1-p300-HDAC3 complex and leads to c-Myc gene activation, likely through recruiting a coactivator (CA) to promote histone acetylation.¹⁷ The stimulatory effects of E1A on YY1-mediated c-Fos gene activation²¹ and ORF50²³ promoter activation, the hepatitis C virus core protein on YY1-mediated B23 gene activation²⁴, and B23 on YY1-mediated proliferating cellular nuclear antigen (PCNA) gene activation^26,27 employ the same model, although the YY1-recruited cofactors are different.

The regulation of another proto-oncogene, c-Fos, also follows the same pattern. Zhou et al²⁰ reported that YY1 inhibits c-Fos gene expression through interaction with the transcription complex activating transcription factor (ATF)/CREB. However, 6 months later, they reported that E1A could reverse this inhibition by disrupting the ATF-CREB-YY1 complex, thereby converting YY1 from a repressor to an activator of the c-Fos gene.²¹ Another report also indicated that YY1 stimulated the association between serum response factor and the c-Fos serum response element,²² suggesting its role in activating c-Fos gene expression. A recent study provided another example of E1A-mediated conversion of YY1 from a repressor to an activator.²³ ORF50 is a crucial gene responsible for the switch from latency to lytic replication of Kaposi’s sarcoma-associated herpesvirus. YY1 represses the ORF50 promoter, but the YY1-E1A fusion protein activates it.

In addition to E1A, YY1-regulated expression of B23/nucleophosmin can be modulated by a viral gene product, the hepatitis C virus (HCV) core, which plays an important role in liver oncogenesis.²⁴ The interaction between the HCV core and YY1 leads to the recruitment of p300 and B23 to the YY1 consensus binding site on the B23 promoter and activates gene expression. However, in the absence of the HCV core, YY1 recruits HDAC1 to repress the B23 gene. Because B23 exhibits oncogenic effects by suppressing multiple tumor suppressors,²⁵ this study strongly suggests a stimulatory role of YY1 in liver oncogenesis.

Interestingly, like E1A, B23 also can convert YY1 from a transcriptional repressor to an activator²⁶ and promote the YY1-mediated activation of proliferating cellular nuclear antigen (PCNA).²⁷ These studies provided additional evidence of oncogene-mediated YY1 activation. Overall, YY1 does not always activate, and may even repress, the expression of oncogenes; however, its activating or stimulatory effects on the expression of these oncogenes can be triggered by proliferative or oncogenic signals, such as E1A (Fig. 1).

The androgen receptor (AR) regulates cell differentiation in normal prostate development, but it also plays a crucial role in prostate cancer progression.²⁸ We reported that YY1 interacted with AR and was essential for its optimal transcriptional activity. However, AR-mediated transcription was not enhanced when YY1 was expressed ectopically because YY1 already is overexpressed in prostate cancer cells. This result suggests that the overall levels of YY1 should be maintained within a certain range to achieve its regulatory function.²⁹

YY1 also reportedly activates the expression of human epidermal growth factor receptor (HER) 2 (ERBB2, neu),^30,31 which is overexpressed in approximately 30% of breast cancers and correlates with poor prognosis.³² Both gene amplification and transcriptional activation contribute to HER2 overexpression in cancers.³³ However, YY1 overexpression is more prevalent in breast tumors without HER2 gene amplification, suggesting it has a role in promoting HER2 gene expression.³¹

Glucose regulating protein (GRP) 78/binding immunoglobulin protein is a prosurvival endoplasmic reticulum (ER) chaperone and exhibits oncogenic activities including promoting tumor growth, survival, metastasis, and resistance to therapeutic treatments.³⁴ YY1 acts as a transcriptional coactivator of ATF6 and recruits PRMT1 to mediate histone H4 methylation, which leads to GRP78 gene activation.³⁵ A later report also indicated that GATA-4 was essential to YY1-mediated GRP78 activation.³⁶ Because YY1 binds only to the GRP78 promoter under ER stress conditions, this study indicates that YY1 promotes cell survival in response to cellular stresses.

Vascular endothelial growth factor (VEGF) is the key mediator of angiogenesis in cancer and is an essential target of cancer therapy. YY1 forms an active complex with hypoxia-inducible factor (HIF) 1α to activate VEGF gene expression, whereas YY1 depletion reduces systemic neoangiogenesis in vivo during metastasis.³⁷ YY1 induces expression of cyclooxygenase-2 (COX-2), which is overexpressed in 40% of human invasive breast cancers and mediates bone metastasis.³⁸ As a homeobox gene, OTX2 is essential in head development and acts as an important oncogenic driver in medulloblastoma. Acetylated YY1 binds to the enhancer sequence of the OTX2 gene and activates its expression.³⁹

Several studies have suggested a regulatory role of YY1 in epithelial-mesenchymal transition (EMT). EMT can be induced by multiple oncogenic pathways and is inhibited by the tumor invasion suppressor E-cadherin. As a transcription factor, Snail inhibits E-cadherin expression during development and tumorigenesis. YY1 binds the 3′ enhancer of Snail and is essential to Snail expression in melanoma cells.⁴⁰ However, YY1 does not directly regulate Snail-mediated E-cadherin transcription, although a YY1 binding region is present in the E-cadherin promoter.^41,42 Another report demonstrated the activity of YY1 in mediating the transcriptional activation of a homeobox gene, Msx2, which plays an important role in promoting EMT in different cell types.⁴³

Other recent studies also suggested the involvement of YY1 in cancer development. YY1 activates the GDAP1 gene, which is highly expressed in cancer cells originating from different tissues.⁴⁴ In bladder cancer, YY1 seemed to regulate commonly the expression of down-regulated genes in T1-grade II disease and simultaneously in T1-grade III disease.⁴⁵ YY1 and cyclin-dependent kinase 6 both were correlated positively with RNA levels of E6/E7, a classic oncogene complex.⁴⁶

The studies summarized above describe oncogenes activated by YY1. There are also some reports indicating that YY1 mediates the activation of genes with tumor-suppressive functions. Although the negative regulation of p53 at the posttranslational level has been demonstrated by multiple groups,^47–52 an early report suggested that overexpressed YY1 could stimulate the expression of a p53 promoter reporter and that this activation could be enhanced by co-transfected E1A.⁵³ These results contradict the well-established oncogenic function of the E1A protein. Another report also indicated that YY1 and E2F1 cooperatively mediate the transcriptional activation of the p73 gene.⁵⁴ Overexpressed YY1, together with activator protein 1, activated transcription of HLJ1, a suppressor of tumor invasion.^55,56 A recent study from Lee et al⁵⁷ indicated that YY1 transactivates the promoter of breast cancer 1 (BRCA1), a tumor suppressor gene. In breast cancer samples, YY1 positively correlates with BRCA1 expression.

The important role of YY1 in maintaining cellular activities including epigenetic changes and malignant transformation can be shown by its regulation in histone synthesis and cell respiration. YY1 promotes the expression of several histone proteins. Eliassen et al⁵⁸ reported that YY1 binds a histone DNA element, H3.2α, and regulates the expression of histone H2a and H3 proteins. Last et al⁵⁹ also demonstrated that YY1 contributes to histone H4 gene transcription. Cunningham et al⁶⁰ investigated the role of YY1 in mediating cell respiration through mitochondria. They observed that YY1-binding elements are enriched greatly in mitochondrial genes, and YY1 silencing markedly decreases the expression of many mitochondrial genes and in turn compromises oxygen consumption. Consistently, YY1 protein is necessary for the rapamycin-mediated inhibition of mitochondrial genes. Mechanistic studies have indicated that the YY1-PGC-1α transcriptional complex is essential to the mitochondrial oxidative function, while mTOR interferes with this regulation through altering the YY1-PGC-1α complex. Overall, this study suggests that YY1 is involved in maintaining the basal respiration of cells. More YY1-activated genes related to tumorigenesis are shown in Table 1.

B. Yin Yang 1–Repressed Gene Expression

The YY1-repressed genes that are related to cancers are listed in Table 2. Most previous studies have indicated that YY1 represses gene expression through regulating histone deacetylation and H3-K27 methylation. Recently, Yu et al⁶¹ demonstrated that YY1 recruits BRCA1 associated protein 1 (BAP1), a de-ubiquitinating enzyme, to mediate gene silencing. In addition to histone modifications, YY1 also may regulate DNA methylation. As a tumor suppressor, CCAAT/enhancer-binding protein δ (CEBPD) inhibits cell differentiation and promotes apoptosis. In cancer cells, YY1 represses CEBPD gene expression through regulating the methylation of its promoter. Epigenetic silencing of CEBPD is achieved by YY1-mediated recruitment of a repressive complex (including SUZ12, Ezh2, DNMT1, DNMT3A, and DNMT3B) to the 2 YY1-binding motifs on the CEBPD promoter. Mutations of either of these motifs will abolish the regulation of these histone and DNA modifiers.⁶²

TABLE 2.

Yin Yang 1–Repressed Genes/Promoters

Gene/Promoter	Function of the Gene Product	Mechanism/Observation	Reference
A. Oncogenic and/or overexpressed genes
Lymphoid enhancer-binding factor-1	Mediates tumor cell invasion	YY1 depletion activates the gene expression and reduces H3-K9 tri-methylation	217
interferon β	Potential target in cancer therapy	YY2 antagonizes the repression by YY1, Sin3A/NCoR/HDACs complex is recruited by YY1	108,218
Has2	Oncogenic role	Together with SP1; O-GlcNAc modification alteres this regulation	139
Hypoxia-inducible factor-2α (HIF-2α)	Oncogenic role	Phosphatase and tensin homolog released this repression	97
HOXB13	Promotes cancer progression	HDAC4 is recruited	83,219
Hepatitis B virus pre-S mutants	Viral oncoproteins	A feedback inhibition of the mammalian target of rapamycin activation; HDAC1 is recruited	220
MAT2A	Upregulated in cancers; potential oncogenic role	Insulin-like growth factor-1 stimulates YY1-binding to the promoter	145
Matrix metalloproteinase-9	Increasingly expressed in various cancers	Mono-ubiquitinated YY1 binds C-terminal binding protein; HDAC3 is recruited	102
ORF50 promoter	Regulates lytic replication of Kaposi sarcoma-associated herpesvirus	Fusion of E1A with YY1 activates the ORF50 promoter	23
PVT1	Oncogenic role	A mutation leading to reduced YY1 causes PVT1 overexpression	221
Steroidogenic acute regulatory	Related to some cancers, e.g., glial tumors	HDAC1 is recruited	222,223
B. Tumor suppression genes
CCAAT/enhancer-binding protein δ (CEBPD)	Tumor suppressor	Recruit enhancer of zeste homolog 2, DNMT1, DNMT3A, DNMT3B	62
Chondromodulin-I	An angiogenesis inhibitor	HDAC2 is recruited by YY1	67
Death receptor 5 (DR5)	Receptor in extrinsic apoptosis pathway	Rituximab inhibits DNA binding of YY1 and releases this repression	68,154
KISS1	Metastasis suppressor	Sp1 is not involved.	66
microRNA-29	Tumor suppressor of rhabdomyosarcoma	Through binding to a conserved regulatory region	70
microRNA-206	Promotes cell apoptosis	c-Jun and c-Fos antagonize this regulation	71
p21	Leads to cell cycle arrest	YY1 antagonizes p53-mediated transcription	49,65
p16(INK4a)	Tumor suppressor	HDAC3 and HDAC4 are recruited	64
Peg3 and Usp29 (via conserved sequence binding element 1)	Peg3: Tumor suppression Usp29: ubiquitin-specific protease 29	Multiple YY1-interacting sites are detected	197
Retinoblastoma	Tumor suppressor	GA binding protein and host cell factor 1 are involved in this regulation	63
C. Other regulatory proteins related to cancers
α3β1-integrin	Contradictory role in cancer invasion	c-Myc, cyclic adenosine monophosphate response element binding, and HDACs are involved	170
CD30	A member of the TNF receptor family; related to lymphoma	Directly binds the promoter	224
CXCR4, CXCR7	Chemokine receptor; related to breast cancer cell migration	The regulation is regulated divergently by hypoxia	225,226
PPAR-δ	Nuclear receptor proteins regulate gene expression	Directly binds the promoter	227
ERCC5/XPG	DNA repair gene	E2F1 is involved in this regulation	228
Cyclin D1	Regulates Cdk4 function	HDAC1 is recruited	65,229
Involucrin	A marker of differentiation	c-Jun is involved in this regulation	230–232
Hoxd4	Regulates morphogenesis	MEL18 also recruited	233

DNMT, DNA methyltransferase; HDAC, histone deacetylase; YY1, Yin Yang 1.

Many other YY1-inhibited genes exhibit tumor suppressive potential. YY1 binds the promoter of retinoblastoma (Rb) protein and cooperates with GA binding protein to repress Rb gene expression (Fig. 2A). During myogenesis, YY1 translocates from the nucleus to the cytoplasm, leading to Rb gene activation.⁶³ YY1 negatively regulates tumor suppressors p16 and p21.^49,64,65 In addition, YY1 interferes with p53-mediated transcriptional activation by attenuating the expression of its target genes.⁴⁹ Recently, YY1 was shown to repress expression of the KiSS1 and chondromodulin-I genes, which inhibit tumor metastasis and angiogenesis, respectively.^66,67 YY1 also down-regulates death receptor (DR) 5, a key component in the extrinsic pathway of apoptosis, and consequently confers therapeutic resistance to tumor cells.⁶⁸ In hepatocellular carcinoma, overexpressed YY1 negatively correlates with Raf kinase inhibitor protein (RKIP), a metastasis-suppressor. The YY1/RKIP mRNA ratio was inverted profoundly in tumors compared with adjacent normal tissues.⁶⁹

FIGURE 2.

Schematic model of the interplay between Yin Yang 1 (YY1) and retinoblastoma (Rb). A, YY1 negatively regulates Rb gene transcription. YY1 and GA binding protein (GABP) cooperatively repress Rb gene expression, likely through recruiting a co-repressor (CR). During myoblast differentiation, YY1 is translocated from nucleus (Nu) to cytoplasm (Cy). This leads to the recruitment of host cell factor (HCF)–1 and probably a co-activator (CA), and Rb gene activation.⁶³ B, Rb negatively regulates YY1-activated c-Myc gene expression. In human Burkitt lymphoma cells, a translocated c-Myc allele is regulated by the immunoglobulin heavy-chain gene HS3 enhancer. In resting or normal cells, hypophosphorylated Rb binds YY1 and prevents its association with HS3. In Burkitt lymphoma cells, YY1 disassociates with Rb, binds to the HS3 enhancer, and recruits a histone acetyltransferase (HAT) to mediate the acetylation of the c-Myc promoter, which leads to c-Myc gene activation.¹⁹ Phosphorylation of Rb causes its disassociation with YY1.¹¹² The O-GlcNAcylation of YY1 both disrupts the Rb-YY1 association and increases the DNA binding affinity of YY1.^111,139,140

Several groups reported the role of YY1 in mediating microRNA (miR) expression. YY1 inhibits the expression of both miR-29 and miR-206.^70,71 These 2 miRs possess tumor-suppressive activities through activating p53 and promoting cell apoptosis, respectively.^72,73 On the other hand, YY1 promotes the expression of miR-190 that is upregulated in liver and pancreatic cancers and may play a role in AKT activation.^74,75

YY1 binding elements are present in more than a thousand promoters of vertebrate genes.⁷ The overall effect of YY1 on the expression of a particular target gene depends on the extracellular stimuli and the availability of coactivators or corepressors, which may vary greatly in the cell lines employed in different studies. To interpret the data correctly, we should consider the following issues:

1. When YY1 is overexpressed robustly by transient transfection, the cofactors involved in the YY1-coordinated transcription can become saturated or even insufficient; some other proteins that are not involved in normal conditions or at regular YY1 levels may play a role to impact gene expression. Therefore, studies that examine only YY1 overexpression, typically through transfection, may generate artificial results. Such results should be confirmed by other approaches, such as different dosages of ectopic gene expression or gene silencing.

2. In the endogenous scenario, the transcriptional activities of YY1 largely are accomplished through mediating chromatin remodeling, including various histone modifications and promoter methylation. However, these chromatin modulations are unlikely to occur on transfected plasmid DNA in reporter assays, which have been used in many studies of YY1 transcriptional regulation. Studies of the endogenous genes or at least genome-integrated reporter cassettes are more reliable.

3. In some reports, YY1 was overexpressed ectopically in cancer cells, most of which already had increased levels of YY1. The antiproliferative effects observed in these conditions would not represent the physiologic consequences of YY1 alterations. Instead, ectopic YY1 expression in normal or non-tumorigenic cells using promoters with medium strengths, or its silencing in tumor cells, would be more accurate and logical in these studies.

Although it is difficult to judge YY1 solely as an oncogene or tumor suppressor based on the genes that YY1 transcriptionally regulates, the tumor-promoting effects of YY1-mediated transcriptional regulation clearly override its role in tumor suppression. It is likely that the overall regulation of YY1 in tumorigenesis may rely on the oncogenic stimuli, cell types, and the interplay with its recruited cofactors, the availability of which may alter at different physiologic conditions.

III. YIN YANG 1 ACTIVITIES INDEPENDENT OF ITS DNA BINDING ACTIVITY

YY1 initially was identified as a transcription factor to bind DNA directly and mediate gene expression.¹ However, the regulatory activities of YY1 independent of its DNA binding increasingly have been appreciated.¹¹ Certainly, these activities of YY1 also may play a role in regulating gene expression.

A. Yin Yang 1–Mediated Protein Posttranslational Modifications

YY1 interacts with many proteins that mediate posttranslational modifications, which largely has expanded the complexity of YY1-regulated biological processes. These YY1-interacting protein modifiers include HDACs, p300/CBP, Ezh2, Ezh1, protein inhibitor of activated STAT Y (PIASy), Ubc9, murine double minute 2 (Mdm2), and BAP1. Many of these YY1-interacting partners mediate YY1-regulated gene expression; however, they are involved in non-transcriptional activities. Meanwhile, the observations of YY1 translocation between nucleus and cytoplasm at different cell cycle stages strongly suggest that YY1 is involved in biological processes besides the regulation of gene expression.^76,77

YY1 has been reported to interact with numerous proteins, including many protein modifiers that promote acetylation, deacetylation, methylation, ubiquitination, de-ubiquitination, and sumoylation of histone or nonhistone proteins. A well-established mechanism of YY1-regulated gene expression is through recruiting histone modifiers to the target promoters and modulating histone modifications.

1. Acetylation

YY1 was first demonstrated to interact with p300 by Lee et al⁷⁸ in 1995. Importantly, YY1 and E1A bind to different domains of p300, whereas the binding sites of p300 and E1A on YY1 are also different, suggesting the presence of a YY1-E1A-p300 ternary complex. This explains the ability of E1A to convert YY1 from a transcriptional repressor to an activator by bringing in p300 to YY1 and acetylating histones on the YY1 target promoters, including adenovirus P5, c-Myc, and c-Fos.^1,18,21 YY1 inhibits p300-mediated p53 acetylation, which is independent of the transcriptional activity of YY1.⁴⁸ The acetylation of p53 prevents its ubiquitination⁷⁹ and promotes p53 transcriptional activity through enhancing p53-DNA interaction.⁸⁰ Therefore, the negative regulation of p53 acetylation by YY1 implicates its role in antagonizing p53 function.

Yang et al⁸¹ made a landmark discovery by demonstrating YY1-mediated histone deacetylation. They discovered that YY1 interacts with human RPD3, a homolog of yeast RPD3 that is the definition base for the class I HDACs. This human RPD3, determined to be HDAC2,⁶ contributes to YY1-mediated transcriptional repression. Many other studies indicated the involvement of HDACs in YY1-mediated gene suppression. For example, YY1 recruits HDAC2 to the HOXA11 target gene and the chondromodulin-I promoter to repress gene expression.^67,82 YY1 also recruits HDAC4 and represses the expression of HOXB13 that mediates growth arrest in androgen receptor-negative prostate cancer cells.⁸³

2. Methylation

Rezai-Zadeh et al¹⁵ first reported that YY1 recruited PRMT1 to the c-Myc promoter to mediate histone methylation of H4-R3. Later, Baumeister et al³⁵ also demonstrated that YY1-recruited PRMT1 on the promoter of GRP78, a prosurvival ER chaperone protein, leads to histone H4-R3 methylation and GRP78 gene activation. YY1 interacts with 2 lysine-specific histone methyltransferases, Ezh1 and Ezh2, which mediate histone H3-K27 methylation, a hallmark of gene silencing in cancers.⁸⁴ Caretti et al⁸⁵ first demonstrated that YY1 recruited Ezh2 to mediate histone H3-K27 methylation in mouse skeletal muscle cells. Wilkinson et al⁸⁶ conducted elegant studies to map the YY1-Ezh2 interaction and determine its biological roles. They carried out transgenic studies in Drosophila to demonstrate that the recruitment of Polycomb proteins motif, consisting of residues 201 to 226 of YY1, is necessary and sufficient to recruit Ezh2 and other Polycomb group (PcG) proteins to establish transcriptional repression.⁸⁶ They also indicated that YY1 associated factor 2, a Drosophila ortholog of Ring1 and YY1 binding protein (RYBP), acts as a molecular bridge between YY1 and other PcG complex proteins.⁸⁷ A more recent study indicated that the p38α kinase-mediated phosphorylation of Ezh2 at r372 promotes the recruitment of Polycomb repressive complex 2 by YY1.⁸⁸

Many studies have suggested the concurrence of histone modifications and DNA methylation.⁸⁹ YY1-mediated gene silencing of the tumor suppressor CEBPD is a good example of this multiple-level regulation. To inhibit CEBPD expression, YY1 recruits PcG proteins SUZ12 and Ezh2, as well as 3 DNMTs (DNMT1, DNMT3A, and DNMT3B), to mediate the methylation of both histone H3-K27 and the CEBPD promoter.⁶²

3. Ubiquitination and Sumoylation

Several groups have demonstrated the negative regulation of p53 by YY1. YY1 directly interacts with both p53 and Mdm2, a ubiquitin E3 ligase, and enhances Mdm2-mediated p53 ubiquitination and degradation.^47,48 YY1 depletion leads to either apoptosis or cell cycle arrest, depending on the cell types.^47,50,90 Importantly, this regulation is independent of the transcriptional activity of YY1 because a YY1 mutant deficient in DNA binding retains the ability to stimulate p53 ubiquitination, and purified YY1 protein can promote p53 ubiquitination in vitro.⁴⁷ A previous study indicated that YY1 promotes the expression of cytochrome c oxidase subunit 7C, regulating mitochondrial respiration.⁹¹ Recently, Yu et al⁶¹ demonstrated that this activation is mediated by the YY1-recruited deubiquitination enzyme BAP1 to the cytochrome c oxidase subunit 7C promoter.

Protein sumoylation may have consequences quite different from ubiquitination.⁹² The conjugation of small ubiquitin-related modifier (SUMO) may alter protein interaction, stability, and activity.⁹³ We reported that the Lys288 residue of YY1 (Fig. 3) is a target for the conjugation of 3 different SUMO proteins (SUMO-1, -2 and -3).⁹⁴ Sumoylation of YY1 can be catalyzed by a SUMO E3 ligase PIASy and can inhibit YY1 transcriptional activity. The SUMO conjugating enzyme Ubc9 also directly interacts with YY1. This study revealed the potential of YY1 in mediating sumoylation of its recruited proteins and thereby modulating expression of its target genes.

FIGURE 3.

Domain structure of human Yin Yang 1 (YY1) protein with indicated posttranslational modification sites or regions. Polo-like kinase 1 (Plk1) phosphorylates T39,¹³⁷ while protein inhibitor of activated STAT Y (PIASy) stimulates the sumoylation at K288.⁹⁴ p300 and PCAF mediate the acetylation of residues 171–200, while P300/CBP associated factor (PCAF) also acetylates the C-terminal.¹³⁸ Phosphorylation of Thr348 and Thr378, but not Ser247, reduces the DNA binding affinity of YY1.⁷⁷ The regions of the 32 lysine residues are indicated. The sequence of YY1 protein is based on the NCBI access number NM_003403.3. The figure is adapted from Sui¹⁰ with permission.

B. Yin Yang 1 as a Transcription Cofactor

Most YY1-related studies present YY1’s transcriptional activities on the genes or promoters containing YY1 binding elements. However, several recent reports, including ours, demonstrated the role of YY1 as a transcription cofactor independent of its DNA binding. We observed a YY1-dependent expression of prostate-specific antigen (PSA) in prostate cancer cells and a mutation of the YY1 binding element in the PSA promoter did not alter this regulation.²⁹ Moreover, YY1 directly interacts with androgen response (AR) and promotes the association of AR with an AR element, but a YY1 mutant deficient in AR binding loses this effect. Importantly, AR binds to the YY1 C-terminal,²⁹ its DNA binding domain. Therefore, it is unlikely that YY1 concurrently interacts with both the PSA promoter and AR protein. Overall, YY1 acts as a coactivator to promote AR-mediated PSA expression.

Several other studies also demonstrated the activities of YY1 independent of its DNA binding. YY1 represses the expression of the RNA methyltransferase like 1 gene without its own consensus binding site; this regulation depends on ATF/CREB.⁹⁵ YY1 enhances the HOXA11-DNA association and is required for the recruitment of HDAC2 by HOXA11.⁸² YY1 acts as a co-repressor for the transcription factor GON4L.⁹⁶ Also as a co-repressor, YY1 represses HIF-2α expression, which can be relieved by phosphatase and tensin homolog (PTEN)–mediated suppression of YY1.⁹⁷

These studies indicate that YY1-mediated gene expression does not always require the direct binding of YY1 to target promoters, and they have extended our understanding of YY1’s role in gene transcription. Compared with a transcription factor, the cofactor YY1 will have different opportunities to expose its functional motifs and recruit other proteins to mediate gene expression. In this scenario, YY1 can provide a platform for the assembly of a scaffold with different transcriptional machineries where many other cofactors are recruited and assembled.⁹⁰ Importantly, the involvement of multiple YY1-interacting protein modifiers may alter the posttranslational modification status of other factors and in turn determine the expression of a target gene.

C. Other Yin Yang 1–Regulated Processes With Unclear Mechanisms

A number of reports have described other YY1-involved biological processes, but the detailed mechanisms have not been studied. In a human keratinocyte cell line, YY1 inhibited cell differentiation in a 3-dimensional cell culture system.⁹⁸ Wu et al⁹⁹ also reported that YY1-depleted spermatocytes exhibited univalent formation, increased aneuploidy, and pachytene cell death, likely due to defects in DNA repair. Overall, YY1 is likely to be involved in many more signaling pathways not yet identified.

IV. YIN YANG 1-ASSOCIATED PROTEINS

Numerous proteins have been reported to associate with YY1; most are involved in different signaling pathways related to cancer development and progression. We categorize these YY1-associated proteins into 4 groups, as shown in Table 3.

TABLE 3.

Yin Yang 1 Interacting Proteins

Protein	Function	Reference
A. Modifiers of histones and nonhistone proteins
p300, CREB binding protein	Acetylation of histone and nonhistone proteins	78
Histone deacetylases (HDACs) 1, 2, 3, 4, 5	Deacetylation of histone and nonhistone proteins	81,83,138,234,235
Ezh1	Histone methyltransferease	84
Ezh2	Histone methyltransferease on H3-K27 and H1-K26	85,236
Protein arginine methyltransferase 1 (PRMT1)	Histone methyltransferease on H4-R3	15
Mdm2	Ubiquitination of p53 and histones	47,48
Ubc9	E2 conjugating enzyme of sumoylation	94
Protein inhibitor of activated STAT Y (PIASy)	E3 ligase of sumoylation	94
B. Other chromatin remodeling proteins
B23/Nucleophosmin	A histone chaperon involved in nucleosome formation	26
C-terminal binding protein1 (CtBP1)	A corepressor involved in chromatin remodeling	100,101
Ring1 and YY1 binding protein (RYBP)	A repressor present in PcG complex	104
CTCF	Chromatin remodeling; its deregulation causes epigenetic imbalance in cancer	237,238
INO80	Chromatin remodeling and DNA repair	109,110
Sin3-associated protein 30 kDa (SAP30)	Involved in loss of heterozygosity	107,108
C. Tumorigenesis and apoptosis
p53	Tumor suppression and genome stability	47
Retinoblastoma (Rb)	Tumor suppression and genome stability	113
p14ARF	Tumor suppression	47
E1A	Oncogene leading to tumorigenesis	1
Mdm2	Oncogene enhancing p53 degradation	47,239
c-Myc	Oncogene transforming cells	240
c-Jun	Proto-oncogene	116
Caspases* 1, 3, 5, 6, 7	Proteases activated during apoptosis	117
Poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1)	Posttranslational modification, DNA repair	142
E2F2, E2F3	Regulation of retinoblastoma pathway	105
MBP1	c-Myc promoter binding protein 1	186
α-enolase	Tumor antigen in lung cancer	186
Integrases of human immunodeficiency virus and leukemia-related virus	YY1 enhances integrase activity	241
D. General and other regulation
RNA Pol. II, TFIIB, Sp1, activating transcription factor/cyclic adenosine monophosphate response element binding, TAFII55	General gene transcription	20,118–121
Notch1 receptor	Cell fate determination during embryonic development	186,242
SFMBT2	A member of Polycomb group proteins	243
YY1AP (HCCA2)	Hepatocellular carcinoma-specific protein	244–246
YY1 associated factor 2 (YAF2)	Interacts with MycN in neuroblastoma	247,248
mTOR (FRAP1)	Key factor in transducing various stimuli to regulate a wide range of cellular functions	60
Raptor	Associated with mTOR; regulates its expression and kinase activity	60
PGC-1α	A coactivator of YY1 in regulating mitochondrial genes	60
Small and large hepatitis delta virus antigens (σ-virus antigen)	Involved in TGF-β and c-Jun-induced signaling cascade	249
HOXA11	Regulates uterine development	82
Activator protein 2 (AP-2)	Acts as a cofactor to stimulate ERBB2 promoter	30
CP2	Transcription factor; interacts with the HXPR motif of YY1	250
SMAD1/4	TGF-β signal pathway	251

CREB, cyclic adenosine monophosphate response element binding; Ezh, enhancer of zeste homolog; Mdm2, murine double minute 2; mTOR, mammalian target of rapamycin; TGF, transforming growth factor; YY1, Yin Yang 1.

A. Proteins Regulating Modifications

As we have discussed, YY1 interacts with multiple modifiers that regulate protein acetylation/deacetylation (p300, CBP, PCAF); methylation (Ezh2, Ezh1, PRMT1); sumoylation (Ubc9, PIASy); and ubiquitination/deubiquitination (Mdm2, BAP1). The functional roles of these interactions are described in other sections in which these proteins and their regulation are discussed.

B. Other Chromatin Remodeling Regulators

Functional interplay between YY1 and many other proteins involved in chromatin remodeling has been demonstrated. As a nucleolar protein and histone chaperone, B23 regulates nucleosome formation and inhibits numerous tumor suppressors.²⁵ B23 interacts with YY1 and relieves YY1-mediated transcriptional repression.^26,27 YY1 is one of a few members in the PcG that directly bind DNA and recruit other PcG proteins to establish gene silencing. Using Drosophila as a model, Srinivasan and Atchison¹⁰⁰ and Atchison et al¹⁰¹ demonstrated that the gene repression mediated by YY1 and other PcG proteins requires the transcriptional co-repressor C-terminal binding protein (CtBP). In rat hippocampal cells, CtBP specifically interacts with mono-ubiquitinated YY1 to repress matrix metalloproteinase-9 (MMP-9) gene transcription.¹⁰² Therefore, YY1 de-ubiquitination resulting from neuronal depolarization disrupts the repressive complex of YY1-CtBP-HDAC3 and in turn activates MMP-9 expression. A recent study from Basu and Atchison¹⁰³ also indicated that CtBP levels regulate DNA binding affinity of YY1 and its PcG recruitment to DNA.

RYBP initially was identified as a co-repressor in the PcG complex.¹⁰⁴ A later study indicated that RYBP mediates the interaction of YY1 with E2F proteins, which leads to activation of the Cdc6 gene.¹⁰⁵ At the protein level, RYBP mediates the recruitment of PcG complex by YY1.⁸⁷ Interestingly, RYBP antagonizes Mdm2-mediated p53 ubiquitination,¹⁰⁶ in opposition to the effects of YY1.

As discussed above, YY1 can assemble a multifunctional complex to coordinate histone modification and DNA methylation. To repress tumor suppressor CEBPD, YY1-recruited SUZ12, Ezh2, DNMT1, DNMT3A, and DNMT3B form a repressive complex on the CEBPD promoter.⁶²

Sin3-associated protein 30 kDa (SAP30) is a component of the human histone deacetylase complex. The interaction between SAP30 and YY1 can regulate YY1-mediated gene repression.¹⁰⁷ SAP30 promotes the recruitment of HDAC1 by YY1 to repress gene expression. In addition, the recruitment of the Sin3A/nuclear receptor co-repressor/HDACs repressor complex by YY1 inhibits the expression of the interferon β gene.¹⁰⁸

INO80 is a subfamily of switch 2/sucrose non-fermentable 2 chromatin remodeling proteins and plays regulatory roles in gene transcription, DNA repair, and DNA replication. Two recent studies demonstrated the functional interplay between YY1 and INO80. When YY1 activates transcription of its target genes, INO80 acts as an essential coactivator and helps YY1 to gain access to the target promoters.¹⁰⁹ In addition, YY1 and INO80 are essential to homologous recombination-based DNA repair and therefore may regulate the cellular response to genotoxic stress.¹¹⁰

C. Proteins Involved in Tumor Suppression, Oncogenesis, Apoptosis, and DNA Damage

YY1 forms a ternary complex with Mdm2 and p53 to promote Mdm2-mediated p53 ubiquitination and degradation.⁴⁷ In addition, YY1 interacts with many other proteins directly regulating tumorigenesis. YY1 binds to tumor suppressor Rb in vitro; both YY1 glycosylation and Rb phosphorylation can disrupt this interaction.^111,112 In cell-based studies, only hypophosphorylated Rb interacted with YY1, and this interaction reduced DNA binding of YY1,¹¹² implicating a regulatory role of Rb in YY1-mediated transcription. Interestingly, the YY1-Rb complex was observed only in resting cells, not in serum- or lipopolysaccharide-stimulated cells.^112,113 The functional interplay between YY1 and Rb is schematically described in Fig. 2. Whether YY1 inhibits the tumor-suppressive activities of Rb and that YY1-Rb disassociation plays a role in cell proliferation or even malignant transformation is a logical prediction and worthy of further investigation.

YY1 also interacts with the tumor suppressor p14 alternate reading frame (ARF). In functional studies, YY1 competes with p53 to bind to p14ARF and therefore attenuates p14ARF-mediated p53 activation,⁴⁷ which is a separate pathway to antagonize p53 function.

YY1 associates with many oncogene products, including E1A, c-Myc, c-Jun, Mdm2, and B23. As described above, viral oncogene E1A and nucleolar phosphoprotein B23 convert YY1 from a transcriptional repressor to an activator. As a YY1 interacting protein, c-Myc prevents YY1 from associating with its cofactors but does not block its binding to DNA.¹¹⁴ YY1–c-Myc interaction mediates the stimulation of Surf-1 in the mitogen-activated protein kinase cascade.¹¹⁵ Similarly, c-Jun also interacts with YY1 and decreases its binding affinity to its consensus DNA sequence.¹¹⁶

Krippner-Heidenreich et al¹¹⁷ provided evidence of YY1’s involvement in apoptosis. Several apoptotic stimuli could promote rapid translocation of YY1 into the cell nucleus and lead to cleavage of YY1 at Asp12-Gly and Asp119-Gly. Interestingly, one of these N-terminal truncated forms of YY1 could enhance Fas-induced apoptosis, suggesting that YY1 plays a role in positive feedback during apoptosis. An in vitro study showed that YY1 was cleaved by caspases 1, 3, 5, 6, and 7.

D. Other Regulatory Proteins

As a regulatory protein in gene expression, YY1 interacts with many general transcriptional factors and cofactors, such as RNA polymerase II, ATF/CREB, and Sp1.^20,118–121 Consistent with our earlier discussion, this suggests that YY1 both can recruit cofactors to its target promoters and can act as a cofactor recruited by others. Importantly, the presence of YY1 in a transcriptional complex creates an interface for these YY1-interacting protein modifiers that may alter the function of transcriptional machinery by modulating their posttranslational modifications. Therefore, overexpressed YY1 in cancers may contribute to their aberrant epigenetic status and promote cancer development.

V. MECHANISMS REGULATING YIN YANG 1 EXPRESSION AND ACTIVITIES

Although most YY1-related reports have described its role in regulating gene expression and protein modifications, an increasing number of studies have revealed different mechanisms regulating YY1 expression (Table 4). YY1 expression is modulated at multiple levels. Sakhinia et al¹²² and Naidoo et al¹²³ provided striking evidence of the inverse correlation between YY1 mRNA levels and protein expression in follicular lymphoma, suggesting these regulatory mechanisms may have contradictory effects.

TABLE 4.

Factors and Mechanisms Regulating the Function and Expression of Yin Yang 1

Factor	Effect on YY1	Reference
YY1	Negative feedback; binding intron 1	124
Insulin-like growth factor-1	Activation	143
Fibroblast growth factor-2	Activation	146
Hepatitis B virus protein	Activation	56
Tumor necrosis factor-α/NF-κB	Activation	125,126
Morphine	Stimulates YY1 expression	148
Lysophosphatidylcholine (it has proliferative and antiapoptotic effects)	Enhances YY1 expression	149
C/EBP-β	Induces YY1 activity	252
Estrogen-related receptor γ	Induces YY1 expression	71
Interleukin-15	Represses YY1 expression	204
Prohibitin	Represses YY1 (through E2F1 binding site)	129
MicroRNA-29	Inhibits YY1 translation	46,70
MicroRNA-34a	Inhibits YY1 translation	156,157
DETANONOate (nitric oxide donor)	Inhibits YY1 messenger RNA synthesis and YY1-DNA association by causing S-nitrosation of YY1	151,152
Saquinavir	Down-regulates YY1	68,185
Staphylococcal enterotoxin A	Reduces YY1 expression 15-fold in peripheral blood mononuclear cells	153
Naloxone	Down-regulates YY1 expression	148
Raf kinase inhibitor protein (RKIP, a signal transduction modulator and metastasis suppressor)	Down-regulates YY1 via NF-κB inhibition	128,253
Rituximab	Inhibits YY1 expression	127,155
Retinoblastoma Rb	Inhibits DNA binding of YY1	111,140
p53	Inhibits YY1-Sp1-mediated epidermal growth factor receptor activation	103
CtBP1	Necessary for YY1-DNA association	117
Ring1 and YY1 binding protein (RYBP)	A molecular bridge between YY1 and other PcG complex proteins	87
Transforming growth factor-β (TGF-β)	Induces YY1 expression	147
Fentanyl	induces YY1 phosphorylation	74
Probucol	Induces YY1 expression	254
Lipopolysaccharide	Induces YY1 binding to cyclooxygenase-2 promoter	38
Sumoylation/PIASy	Enhances YY1 sumoylation	94
Ubiquitination	Enhances DNA binding and interaction with CtBP, histone deacetylase 3	102
Different apoptotic stimuli and DNA synthesis inhibitor	Causes YY1 translocation and cleavage	76,117
Myeloid nuclear differentiation antigen (MNDA)	Enhances YY1 affinity to DNA	150

CtBP, C-terminal binding protein; NF, nuclear factor; YY1, Yin Yang 1.

A. By Transcription Factors

As a transcription factor, YY1 regulates multiple genes that include itself. Kim et al¹²⁴ recently indicated that YY1 is autoregulated through its own DNA-binding sites in its first intron. They determined that these YY1 binding sites are necessary for YY1 gene transcription, and exogenous YY1 inhibits the expression of the endogenous YY1 gene, suggesting a negative feedback loop.

YY1 expression is enhanced by transcription factor NF-κB that directly binds the YY1 promoter using its subunit p50/p65 heterodimer.¹²⁵ As a result, tumor necrosis factor α (TNF-α) treatment in PC-3 cells stimulated YY1 expression and increased its DNA binding affinity. Meanwhile, genetic deletion of the p65 subunit of NF-κB correlated with reduced YY1 transcripts and protein.¹²⁶ Consistently, rituximab, a chimeric antibody against CD20 that inhibits constitutive NF-κB activity, represses YY1 expression.¹²⁷

RKIP is a metastasis suppressor gene and is expressed poorly in cancers. Baritaki et al¹²⁸ demonstrated that RKIP inhibited YY1 gene transcription. Consistent with this observation, a recent study indicated a negative correlation between YY1 and RKIP expression in hepatocellular carcinoma.⁶⁹ In addition, YY1 expression is inhibited by prohibitin through E2F1 binding sites.¹²⁹

An in vitro study using colon cancer cells indicated that YY1 showed no evidence of gene amplification or chromosomal translocation.¹³⁰ However, 2 YY1 mRNA isoforms (7.5 and 2.9 kb) were overexpressed substantially and aneuploidy was observed.

The promoter of mouse YY1 is guanosine and cytidine (G/C) rich.¹³¹ Our analyses also demonstrated a high G/C content in the human YY1 promoter and a high guanosine content in its 5′-untranslated region (UTR; of mRNA).¹³² Interestingly, the G/C contents of the human YY1 promoter increase monotonically as the analyzed region gets closer to the transcription start site. These features confer the YY1 promoter and 5′-UTR with the potential of forming G-quadruplex (G4) structures. G4 is a 4-stranded secondary structure of DNA or RNA stabilized by Hoogsteen hydrogen bonding of guanine quartets and the stacking of these planar quartets.¹³³ G4 structures typically inhibit gene expression, which can be relieved by resolving enzymes.¹³⁴ Recently, we demonstrated the presence of G4 structures in the YY1 promoter and 5′-UTR that inhibit the transcription mediated by them. Importantly, G4 Resolvase 1 resolves a G4 structure in the YY1 promoter and enhances YY1 expression. Consistently, YY1 levels positively correlated with G4 Resolvase 1 expression in a large cohort of breast cancer patients.¹³²

The promoters of most proto-oncogenes, such as c-Myc and Bcl-2, are guanosine-rich and are regulated negatively by G4 structures in their promoters, whereas the promoters of tumor suppressors are diminished of closely linked guanosine-runs, relative to the genomic average.¹³⁵ The G/C-rich feature and the presence of G4 structures in the YY1 promoter strongly suggest that YY1 is an oncogene.

B. By Posttranslational Modifications

YY1 regulates posttranslational modifications of multiple proteins. Meanwhile, YY1 itself is also a target of many modifications, including phosphorylation, acetylation, sumoylation, and ubiquitination. Among the amino acids that are modifiable, lysines are the targets of acetylation, methylation, ubiquitination, sumoylation, and neddylation. The high lysine content (8%) of YY1 makes it vulnerable to multiple modifications (Fig. 3). Interestingly, among the 414 residues of human YY1, all lysines are located among the 257 residues of its middle and C-terminal regions, but not in the first 157 residues.¹⁰ These modifications regulate the activities, stability, and subcellular localization of YY1.

Rizkallah and Hurt⁷⁷ studied the effects of YY1 phosphorylation on its subcellular localization and transcriptional activities. They identified 3 phosphorylation sites in the YY1 protein: Ser247 in the spacer region and threonines 348 and 378 in the DNA binding domain. Phosphorylation of the 2 threonines, but not Ser247 (Fig. 3), abolished the DNA binding activity of YY1. Similar results were reported by Zheng et al.⁷⁴ They indicated that YY1 phosphorylation induced by fentanyl, an agonist of the μ-opioid receptors, impaired the association of YY1 with the Talin2 promoter. However, a much earlier report indicated that the phosphatase treatment of YY1 could abolish its DNA binding affinity in vitro.¹³⁶ The inconsistency between this study and the first 2 could be due to the different approaches or the presence of unidentified phosphorylation site(s) required for DNA binding of YY1. Very recently, Rizkallah et al¹³⁷ demonstrated that Polo-like kinase 1 phosphorylates YY1 at threonine 39 (Fig. 3) and studied its fluctuation at different cell cycle stages; however, its role in YY1-mediated transcription was not discussed. Another recent study by de Nigris et al³⁷ revealed the potential of AKT-mediated YY1 phosphorylation. YY1 and AKT were detected in the same immunocomplex. Importantly, when sarcoma osteogenic (SaOS) cells were treated by Ly29004, an inhibitor of phosphoinositide 3 kinase and AKT, YY1 exhibited decreased phosphorylation and cytoplasmic accumulation.³⁷

Acetylation regulates the transcriptional activity of YY1.¹³⁸ Both p300 and PCAF enhance the acetylation of the central region (residues 171–200) of YY1 (Fig. 3), and this modification augments YY1-mediated gene repression. PCAF also can cause acetylation of the YY1 C-terminal, which compromises the binding of YY1 to its consensus DNA sequence. Interestingly, HDACs can deacetylate YY1 residues in its central region but not at the C-terminal.

YY1 is a substrate of ubiquitination and sumoylation. YY1 degradation likely is regulated by ubiquitination and proteasomal degradation because the treatment of a proteasome inhibitor led to YY1 protein accumulation.⁴⁷ In neuronal cells, mono-ubiquitinated YY1 interacts with CtBP and HDAC3 to establish a repressive complex that inhibits MMP-9 gene expression.¹⁰² We reported that YY1 can be conjugated by SUMO proteins, which is stimulated by PIASy, a SUMO-E3 ligase. Sumoylation of YY1 exhibited inhibitory effects on its target gene expression.⁹⁴

YY1 is also a subject of other modifications. Some nuclear YY1 can be modified by O-linked N-acetylglucosamine regardless of the differentiation status of the cells, and this modification affects its transcriptional regulation of Has2 gene expression.¹³⁹ Rb inhibits the DNA binding activity of YY1. However, the O-linked N-acetylglucosamine modification of YY1 caused by high glucose exposure disrupts the YY1-Rb association and consequently increases the ability of YY1 to bind to DNA (Fig. 2B).^111,140 YY1 interacts with poly (adenosine diphosphate [ADP]–ribose) polymerase 1 and stimulates its function in catalyzing synthesis of ADP-ribose polymers.¹⁴¹ In addition, YY1 is poly(ADP-ribosyl)ated transiently after genotoxic treatment, which coincides with the activation of poly (ADP–ribose) polymerase 1.¹⁴²

C. By Growth Factors

Multiple growth factors can increase YY1 levels. YY1 expression is stimulated by insulin-like growth factor-1 in fresh media.^143–145 Depletion of insulin-like growth factor -1 by its antibody markedly decreases YY1 levels.¹⁴³ YY1 expression also can be upregulated by fibroblast growth factor-2 during vascular cell injury.¹⁴⁶ Recently, Caggia et al⁵¹ made an interesting observation about differential effects of transforming growth factor (TGF)–β3 treatment on YY1 and p53 expression in 2 prostate cell lines. In benign prostatic hyperplasia cells, TGF-β3 led to increased YY1 and decreased p53 expression; however, in DU-145 prostate cancer cells, TGF-β3 reduced YY1 levels and elevated p53 expression. A recent report also demonstrated the activation of YY1 by TGF-β and proposed a regulatory role of YY1 in pulmonary fibrosis.¹⁴⁷ Proliferative drugs, such as morphine and lysophosphatidylcholine, also could enhance YY1 expression.^148,149 Overall, YY1 levels generally are stimulated by proliferative stimuli, whereas antiproliferative signals tend to antagonize YY1, implicating YY1 as an oncogenic signal-responsive mediator that triggers multiple downstream pathways for malignant transformation.

D. By Other Biomolecules or Mechanisms

Many other molecules or mechanisms can modulate YY1 levels and activities. YY1 expression can be enhanced by lipopolysaccharide,³⁸ and its transcriptional activities can be stimulated by myeloid nuclear differentiation antigen through enhanced YY1-DNA interaction.¹⁵⁰

Several other biomolecules exert negative effects on YY1 expression or function. Different apoptotic stimuli, including the DNA synthesis inhibitor aphidicolin, can translocate and cleave YY1 protein.^76,117 DETANONOate (a nitric oxide donor), naloxone (a drug used to counter the effects of opioid overdose), staphylococcal enterotoxin, probucol (an antihyperlipidemic drug), and rituximab (a chimeric monoclonal antibody against CD20) all inhibit YY1 expression.^{148,151–155}

YY1 expression also can be suppressed by miRs. Although YY1 negatively regulates miR-29 expression, miR-29 also targets the 3′-UTR of the YY1 mRNA and blocks its translation.^46,70 The interplay between YY1 and miR-29 implicates their function in skeletal myogenesis and rhabdomyosarcoma development. Recently, YY1 expression was shown to be down-regulated by miR-34a,^156,157 which has a tumor-suppressive function.¹⁵⁸

In human Burkitt lymphoma cells, YY1 promotes the expression of the translocated c-Myc allele by binding to the immunoglobulin heavy-chain gene HS3 enhancer, which in turn increases c-Myc promoter acetylation.¹⁹ Rb interacts with YY1 to prevent its binding to this enhancer region in normal B cells, but not in Burkitt lymphoma cells, which leads to elevated c-Myc expression in these tumor cells (Fig. 2B).

AKT and PTEN also regulate YY1 expression.⁹⁷ Phosphorylated AKT positively correlates with YY1 levels. The tumor suppressor PTEN antagonizes phosphoinositide 3 kinase/AKT signaling, leading to YY1 down-regulation. Meanwhile, PTEN also may reduce YY1 levels via AKT independent mechanisms.⁹⁷ In Drosophila, CtBP levels control the DNA binding of the YY1 ortholog pho and the recruitment of PcG proteins.¹⁰³

Nguyen et al¹⁵⁹ discovered human YY2 that has 65% similarity in complementary DNA (cDNA) and 56% similarity in protein to human YY1. Because the zinc-finger regions of these 2 proteins are similar, YY2 binds to the same consensus sequence as YY1 but with much lower affinity.¹⁶⁰ Although it has been suggested that YY2 is a retroposed copy of YY1 inserted into another gene locus,¹⁶¹ a more recent study indicated that human YY2 is not wholly redundant to YY1 and could have opposite effects on their shared target genes.¹⁶² Interestingly, silencing of YY2 could reverse the antiproliferative effects of YY1 knockdown, and the depletion of these 2 proteins could cause inverse changes in ultraviolet sensitivity of cells.¹⁶²

VI. YIN YANG 1 EXPRESSION IN CANCERS AND ITS CORRELATION WITH CLINICAL OUTCOMES

As discussed above, YY1 functional studies strongly implicate its regulatory role in tumorigenesis. Meanwhile, ample literature indicates its deregulated expression in different cancers.^163,164 YY1 overexpression has been observed in human breast cancer,³⁰ prostate carcinoma,¹⁶⁵ ovarian cancer,¹⁶⁶ brain cancer,¹⁶⁷ acute myeloid leukemia,¹⁶⁸ osteosarcoma,^169,170 colon cancer,¹³⁰ cervical cancer,^52,171 large B-cell and follicular lymphoma,¹²² and hepatoblastoma.¹⁷² Some mechanisms regulating YY1 overexpression were discussed in the last section.

Seligson et al¹⁶⁵ carried out a comprehensive study using a prostate cancer tissue microarray generated from 1364 representative tissues of 246 hormone-naive prostate cancer patients.¹⁶⁵ They observed YY1 staining in both nucleus and cytoplasm in neoplastic tissues and prostatic intraepithelial neoplasia samples. YY1 exhibited increased expression in early malignancy and tumors of intermediate to high morphologic grade.

In 2008, Thomassen et al¹⁷³ reported that YY1 is upregulated in metastatic breast cancer. In 2009, Powe et al¹⁷⁴ studied a large breast cancer tissue microarray generated from 1176 patients to assess the correlation between YY1 and many biomarker genes. They discovered a positive correlation between YY1 staining and the expression of ER, progesterone receptor, and B-cell lymphoma 2. In agreement with its negative regulation toward p53, YY1 staining also showed inverse correlation to p53 levels. However, inconsistent with previous reports of the positive regulation of HER2 gene expression by YY1,^30,31 Powe et al¹⁷⁴ observed a significant inverse correlation between YY1 and HER2 levels. These conflicting results suggest that other regulatory pathways, in which YY1 may be involved, can counteract or override the stimulatory effects of YY1 on HER2 gene transcription.

Correlation between YY1 overexpression and tumor grades also has been reported in other cancers. In osteosarcoma, YY1 overexpression strongly and positively correlated with the degrees of malignancy.^169,175 In colon cancer, YY1 staining intensity was more pronounced in poorly differentiated tumors than in moderately or well-differentiated colon cancers.¹³⁰

Although YY1 frequently is overexpressed in most cancers, the correlation between YY1 levels and clinical outcomes varies among the diseases in different tissues. In prostate cancer, low nuclear YY1 staining correlated with a shorter time of recurrence, suggesting that YY1 increase was associated with better prognoses.¹⁶⁵ In breast cancer tissues, YY1 staining also showed a significant association with improved breast cancer-specific survival and disease-free interval, but not for distant metastasis or tumor recurrence.¹⁷⁴ In colon and ovarian cancers, YY1 expression positively correlated with the long-term survival periods of patients.^130,166,176

On the contrary, hepatoblastoma patients with high YY1 levels showed a poor prognosis.¹⁷² Sakhinia et al¹²² carried out YY1 studies in follicular lymphoma. They first reported that increased YY1 mRNA levels were associated with a shorter survival interval. However, the later study by Naidoo et al¹²³ indicated that elevated YY1 protein levels in follicular lymphoma patients could be used as a clinical prognostic marker for longer survival. Another group observed the association of YY1 overexpression with B-cell transformation and tumor progression in diffuse large B-cell lymphoma, but the clinical outcomes were not determined.¹⁷⁷

Currently, the reasons for the apparent inconsistencies in YY1’s correlation with clinical outcomes among different cancers are unknown. We predict that the genes differentially regulated by YY1 in these cancers are important determinants of the outcomes or responses in cancer therapies. For example, Matsumura et al¹⁷⁶ indicated that YY1 and E2F overexpression sensitized ovarian cancer cells to the treatment of taxanes, a group of anticancer drugs. Therefore, the enhanced therapeutic response caused by increased YY1 conferred longer survival to these ovarian cancer patients. In breast cancer, YY1 levels positively correlated with ER expression,¹⁷⁴ which is a marker for better prognosis.

VII. YIN YANG 1 AND CANCER THERAPY

Because of its regulatory function in many cancer-related pathways and its overexpression in cancers, the potential of YY1 as a prognostic marker and therapeutic target has been suggested in multiple studies.

YY1 has functional interplay with several tumor suppressors. Importantly, YY1 antagonizes p53 through several distinct mechanisms,¹⁰ including promoting Mdm2-mediated p53 ubiquitination and degradation,⁴⁷ blocking p53 acetylation,⁴⁸ attenuating p14ARF-mediated p53 stabilization,⁴⁷ and inhibiting p53-mediated transcription.⁴⁹ These multiple and consistently negative regulatory mechanisms mediated by YY1 implicate p53 as a primary target of overexpressed YY1 in cancer cells. Although p53 mutations or deletions can be detected in more than 50% of cancers, more than 40% of tumors retain functional p53, and some cancers only have p53 inactivation at late stages. Therefore, most tumors still need to defeat p53-mediated tumor surveillance in their early stages. We predict that YY1 may play a role in this process. YY1 also negatively regulates p14ARF-mediated p53 activation and represses the expression of p16 and p21^49,64,65. On the other hand, dephosphorylated Rb binds YY1 and mediates its DNA binding¹¹², although it is still unclear whether YY1 has any impact on the tumor-suppressive function of Rb. PTEN also down-regulates YY1 expression and its transcriptional regulation toward HIF-2α.⁹⁷

YY1 promotes the functions and expression of multiple oncogenes. Ezh2 has been identified as a bona fide oncogene¹⁷⁸ and has been used as a marker of cancers with aggressive or metastatic potential. In functional studies, Ezh2 was required for cancer progression and invasion,^179,180 and its overexpression increases the likelihood of therapeutic failure.¹⁸¹ YY1 recruits Ezh2 to target promoters; its overexpression in cancers may promote the methyltransferase activity of Ezh2 and establish aberrant epigenetics, which augments cancer progression. Meanwhile, YY1 activates the expression of c-Myc and c-Fos, especially in the presence of E1A. YY1 expression is stimulated by various growth factors. All these studies implicate a proliferative or oncogenic role of YY1 in cancers.

Multiple studies have suggested the therapeutic potential of YY1 in cancer treatment. The Bonavida group¹⁸² extensively studied the role of YY1 in chemo- and immunoresistance in cancer therapy and indicated that YY1 levels were related to therapeutic responsiveness. YY1 negatively regulates the expression of Fas, a transmembrane surface receptor of the tumor necrosis factor receptor family. Therefore, nitric oxide or rituximab treatment inhibited YY1 expression, which, consequently, could upregulate Fas and sensitize tumor cells to Fas-induced apoptosis.^152,183 YY1 also represses the expression of DR5. In prostate cancer and B-cell non-Hodgkin lymphoma, DR5 down-regulation caused by YY1 overexpression makes the tumor cells resistant to the treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Rituximab inhibits both the DNA binding and expression of YY1 and leads to DR5 upregulation, which also sensitizes TRAIL–induced apoptosis.^154,155 Consistently, tumor cells with resistance to rituximab still maintained high levels of YY1.¹⁸⁴ Recent studies from Mijatovic et al⁶⁸ and Donia et al¹⁸⁵ demonstrated that Saquinavir-nitric oxide, a drug with enhanced anticancer properties and less toxicity than nitric oxide, dominantly could reduce YY1 expression and consequently upregulate DR5. RKIP-mediated YY1 down-regulation also increased the sensitivity of tumor cells to rituximab.¹²⁸

A study by de Nigris et al¹⁷⁵ focused on the role of YY1 in cell invasion, angiogenesis, and metastasis. Their data indicated that YY1 depletion significantly decreased cell invasion and metastasis growth, which was associated with reduced VEGF and angiogenesis. This finding clearly suggests that YY1 is a promising and effective target in the therapy of bone cancer. A recent study by He et al⁵² demonstrated significantly elevated YY1 expression in cervical cancer tissues. They also observed that arsenic trioxide, an anti-cervical cancer agent, could reduce the levels of both YY1 mRNA and protein. Meanwhile, YY1 depletion significantly enhanced the apoptosis indicated by arsenic trioxide.⁵²

Overall, YY1 has great potential as a target in cancer therapies. Theoretically, simultaneously targeting several pathways related to cancer development should result in a more efficient and prompt outcome than targeting each of them individually. If a regulatory protein contributing to the abnormality of multiple processes toward malignancy can be identified, targeting this key regulator may exhibit a substantial impact by concurrently reversing or adjusting multiple pathways. YY1 is an essential regulatory factor of numerous epigenetic events and its expression may affect many different biological processes leading to tumorigenesis. Therefore, YY1 is likely one of these key regulatory proteins in cancer development and can serve as an effective target in cancer therapies. Targeting or adjusting YY1 potentially can reverse the aberrant epigenetics of cancer cells and restore their normality. This will be especially important to the cancers in critical organs where radical surgery is not applicable.

VIII. CONCLUSION

As reviewed above, YY1 is a key regulator of multiple signaling pathways involved in cancer epigenetics. Although some discrepancies still exist, we conclude that, overall, YY1 is an oncogene based on the following properties: (1) Upon oncogenic stimulation, YY1 activates multiple well-characterized oncogenes, such as c-Myc, c-Fos, B23, and ERBB2; (2) YY1 mediates the functions of many proteins that contribute to aberrant epigenetic alterations in cancers, such as Ezh2, PRMT1, p300, HDACs, and DNMTs; (3) YY1 antagonizes the functions of several key tumor suppressors, such as p53 and p14ARF, through multiple mechanisms; (4) YY1 expression and function are stimulated by proliferative or oncogenic signals, such as various growth factors and AKT; (5) YY1 is antagonized by multiple tumor suppressors (such as PTEN, Rb, and several tumor suppressive miRs) and apoptotic stimuli; and (6) YY1 is overexpressed in most cancer types and its promoter contains G4-forming structures that typically are present in the promoters of oncogenes. However, because of the complex regulatory role of YY1 in multiple signaling pathways, YY1 levels may correlate with either good or poor clinical outcomes of patients, depending on cancer types.

ABBREVIATIONS

AP-1

activator protein 1

AR

androgen receptor

ARE

androgen response element

BAP1

BRCA1 associated protein-1

BRCA1

breast cancer 1 (a tumor suppressor gene)

CEBPD

CCAAT/enhancer-binding protein δ

ChM-I

chondromodulin-I

COX-2

cyclooxygenase-2

COX7c

cytochrome c oxidase subunit 7C

CtBP

C-terminal binding protein (a transcriptional co-repressor)

DNMT

DNA methyltransferases

DR5

death receptor 5

EMT

epithelial-mesenchymal transition

ER

estrogen receptor

Ezh2

enhancer of zeste homolog 2

G4

G-quadruplex

H3-K27

histone H3 lysine 27

HCV

hepatitis C virus

HDAC

histone deacetylase

HER2 (neu,ERBB2)

human epidermal growth factor receptor 2

HIF-1α

hypoxia-inducible factor 1-alpha

Mdm2

murine double minute 2

mTOR

mammalian target of rapamycin

NF-κB

nuclear factor-kappaB

PARP

poly (ADP-ribose) polymerase 1

PCAF

P300/CBP-associated factor

PcG

polycomb group

PCNA

proliferating cellular nuclear antigen

PgR

progesterone receptor

Plk1

Polo-like kinase 1

PRC

polycomb repressive complex

PRMT

protein arginine methyltransferases

PSA

prostate-specific antigen

PTEN

phosphatase and tensin homolog (a tumor suppressor gene)

Rb

Retinoblastoma

REPO

recruitment of polycomb proteins

RKIP

Raf kinase inhibitor protein

RNMTL1

RNA methyl-transferase like 1

RYBP

Ring1 and YY1 binding protein

SRF

serum response factor

SUMO

Small Ubiquitin-related Modifier

TGF

transforming growth factor

TRAIL

tumor necrosis factor-related apoptosis-inducing ligand

UTR

untranslated region (of mRNA)

VEGF

vascular endothelial growth factor

YY1

Yin Yang 1