Multifaceted functions of Y-box binding protein 1 in RNA methylated modifications (Review)

Abstract

Y-box binding protein 1 (YBX1/YB-1) is a DNA/RNA-binding protein, which plays a crucial role in promoting tumor progression and resistance to anticancer drugs. YBX1 is widely involved in a range of biological processes such as DNA repair, mRNA transcription, pre-mRNA splicing, mRNA stability regulation, translation and exosome sorting. In addition to these canonical DNA/RNA-binding protein functions, YBX1 can also have a regulatory role in N6-methyladenine (m⁶A) and 5-methylcytosine (m⁵C) RNA modification. Moreover, YBX1 functions as an m⁵C reader to regulate mRNA stability, thus modulating gene expression and affecting disease development. Furthermore, SU056, an inhibitor of YBX1, has been shown to reverse drug resistance and prevent tumor development. In the present review, the structure of YBX1 and its functions in RNA methylation modifications are summarized, and its effects on m⁵C and m⁶A RNA modifications in cancer progression and drug resistance are emphasized.

1. Introduction

Recent research has indicated that Y-box binding protein 1 (YBX1/YB-1) has multifaceted functions in regulating drug resistance, PANoptosis, stress response, ferroptosis and cell proliferation (1–5). YBX1 is identified as an oncogene which is overexpressed and positively associated with poor outcomes and survival in numerous cancers including liver, endometrial, non-small-cell lung cancer (NSCLC), ovarian, breast, gastric cancer, kidney renal papillary and clear cell renal cell carcinoma (4–11). YBX1 performs the roles through the regulation of nucleotide metabolism, pre-mRNA splicing, DNA repair, stress granule formation, transcription and translation, and sorting of microRNAs (miRNAs) into exosomes (12–14). Previous studies have shown that YBX1 also plays a crucial role in regulating RNA methylation modification which affects mRNA stability and translation, including N6-methyladenine (m⁶A) and 5-methylcytosine (m⁵C) RNA modifications (5,15). The performance of these functions depends on the structure and location of YBX1. The structural features of YBX1 are crucial for its diverse functions, mediating interactions with DNA, RNA and protein molecules (3,16).

SU056 has been demonstrated to specifically target and inhibit the YBX1 protein, rendering it a valuable tool for investigating YBX1 inhibition (17–20). Multiple studies have demonstrated that SU056 effectively hinders tumor progression in diverse types of cancer including pancreatic cancer (18), triple-negative breast cancer (17) and ovarian cancer (19,20).

In the present review, the focus is mainly on the function of YBX1 in RNA modification. The mechanisms by which YBX1 is involved in RNA modification, including m⁵C, m⁶A and RNA editing are clarified, and YBX1 is proposed as a potential therapeutic target. Furthermore, the roles of YBX1 in regulating anticancer drug resistance through RNA modification are discussed, and its functions on tumor progression are encompassed. This provides a research foundation for the development of anticancer drugs targeting YBX1.

2. Structure of YBX1

YBX1 was initially isolated using double-stranded oligonucleotides in a phage λgt11 library screening as the interacting molecule of the MHC class II gene Y-box element (21). In 1992, the murine (m) CCAAT-binding protein was identified and termed mYB-1 (22). The amino acid sequence of mYB-1 has a 95% homology with human YB-1 (22). In addition, YBX1 cDNA was isolated by screening the binding site through the enhancer oligonucleotide of type 18 human papillomavirus in an expression library of HeLa (23). Researchers found that YBX1 is a nuclear protein with a molecular weight of 42 kDa (23). YBX1 is expressed in most tissues, including the liver, spleen, lung and heart (23). Shortly thereafter, it was shown that YBX1 acted as a binding protein of human multidrug resistance 1 (MDR1) gene and regulated MDR1 gene expression in response to adverse environments (24). In humans, YBX1 genes are located on chromosome 1p34 as identified by in situ fluorescence hybridization (25).

YBX1 belongs to the superfamily of the cold shock proteins and is considered to be evolutionarily conserved (26). The structure of YBX1 consists of three distinct domains, the alanine/proline-rich domain (A/P site) in the N-terminal, the cold shock domain (CSD) in the central region and the C-terminal domain (CTD; Fig. 1). The A/P site domain is involved in protein-protein interactions and mediates the assembly of ribonucleoprotein complexes. Additionally, the A/P site domain functions as a regulatory element, modulating the stabilization of RNA-binding proteins (27). The highly conserved CSD facilitates both DNA and RNA binding, plays a crucial role in mRNA translation, and regulates the adaptation of bacteria to low temperatures (28). In previous studies, CSD was identified to contribute to the identification of m⁵C modification, enhancing mRNA stability and promoting translation (29,30). The CTD contains two important domains that mediate the localization of YBX1, the cytoplasmic retention site (CRS) and the nuclear localization signals (NLS), regulating the location of YBX1 between the cell nucleus and cytoplasm in response to cellular stimuli. Furthermore, CTD has been shown to mediate interactions with diverse protein partners and DNA/RNA-binding proteins (27,28). YBX1 is usually localized in the cell cytoplasm due to the stronger influence of CRS compared with that of NLS. The various functions of YBX1 stem from its diverse domains, making it a key DNA/RNA-binding protein.

Figure 1.

Schematic of YBX1 structure. The main domains of the YBX1 protein contain the A/P site, the CSD, and the CTD. The CTD is composed of the CRS and the NLS. The W65 amino acid is necessary for the recognition of m⁵C RNA modification. The F85 amino acid is important for mRNA stability. YBX1, Y-box binding protein 1; A/P, alanine/proline rich domain; CSD, cold shock domain; CTD, C-terminal domain; CRS, cytoplasmic retention site; NLS, nuclear localization signals; m⁵C, 5-methylcytosine.

3. Role of YBX1-mediated m⁵C modification

Mechanism of m⁵C modification

Research has revealed that the cytidine residues at position five of RNA could be methylated by m⁵C methyltransferases, such as the NOP2/Sun RNA methyltransferase (NSUN) protein family (31). During the m⁵C modification, numerous methyltransferases and proteins are involved in this process, including m⁵C writers, m⁵C erasers and m⁵C readers (31,32). In humans, m⁵C writers consist of the NSUN protein family 1–6 and DNA methyltransferase 2, which catalyze cytosine-5 methylation (32). Among them, NSUN2 is considered the most prominent m⁵C methyltransferase (32). The m⁵C erasers contain the ten-eleven translocation (TET) protein family and AlkB homolog 1, histone H2A dioxygenase (32,33). However, the functions of the m⁵C eraser and those of additional eraser proteins require further investigation (33). The m⁵C readers include YBX1, YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and Aly/Ref export factor (ALYREF), and assume the recognition of the m⁵C modification (34,35). In addition, ALYREF is required for the nuclear export of m⁵C-modified mRNA (34). Furthermore, YBX1 can identify m⁵C-modified mRNA in the cytoplasm and maintain mRNA stability (36,37). YTHDF2 can regulate the maturation of m⁵C-modified ribosomal RNA (rRNA) (35).

The m⁵C modification of RNA can affect its stability, which is important for translation (31). It is a common and conserved phenomenon in various RNAs, including non-coding RNAs (ncRNAs) and mRNAs (38). Over the past years, the RNA m⁵C modification has been demonstrated to be linked to diverse diseases, including cancers (32), viral infections (39) and autoimmune diseases (40). For instance, m⁵C-modified SKI like proto-oncogene (SKIL) may facilitate the progression of colorectal cancer (CRC) (41). Liu et al (7) revealed that the m⁵C modification could enhance the expression of E2F transcription factor 1, thus accelerating ovarian cancer development. These findings indicate that the RNA m⁵C modification plays a vital role in disease progression.

m⁵C-mediated YBX1 functions in oncogenesis

In 2019, Chen et al (29) first characterized YBX1 as an m⁵C reader protein on the distribution of m⁵C modifications in human cancer. They identified the amino acid residue W65 as a key component involved in recognizing the m⁵C modification. YBX1 was previously identified as a DNA/RNA-binding protein that performs a proto-oncogene role in cancers. As an m⁵C reader protein, YBX1 plays significant roles, making it a potential therapeutic target in cancer treatment (5,19,29,42–45). For instance, Chen et al (46) identified an NSUN2/YBX1/nuclear factor erythroid 2-related factor 2 (NRF2) axis that promotes resistance to ferroptosis in NSCLC cells. Mechanistically, NSUN2 was demonstrated to enhance NRF2 expression by adding m⁵C modifications to the mRNA in the 5′ untranslated region (UTR). YBX1 was shown to bind to the m⁵C-modified mRNA, which increased the stability of NRF2 mRNA without affecting the translation process (46). This suggests that YBX1 contributes to resistance through m⁵C modification of RNA rather than by influencing MDR1 expression. Similarly, YBX1 can also regulate the stability of solute carrier family 7 member 11 (SLC7A11) mRNA, impacting ferroptosis resistance via m⁵C modification in endometrial cancer (4). YBX1 was shown to bind to m⁵C-modified SLC7A11 mRNA, enhancing its stability and developing ferroptosis resistance (4). The inhibition of YBX1 through ubiquitination was demonstrated to decrease the expression of m⁵C-modified mRNAs, which in turn increased the sensitivity of epithelial ovarian cancer cells to cisplatin (47). Additionally, in EGFR-mutant NSCLC cells, the YBX1/quiescin sulfhydryl oxidase 1 (QSOX1) axis was responsible for mediating resistance to gefitinib. YBX1 was found to be upregulated in cells resistant to gefitinib (5). Furthermore, YBX1 recognized the m⁵C modification in the coding sequence of QSOX1 mRNA, which led to an increase in QSOX1 translation and a corresponding decrease in gefitinib sensitivity in NSCLC cells (5). This indicates that the YBX1-mediated m⁵C modification may contribute to the drug resistance observed in cancer cells, providing novel insights into potential strategies for overcoming this resistance.

YBX1 can not only impact drug resistance through m⁵C modification, but also promote tumor development. In lung squamous cell carcinoma (LUSC), YBX1 recognized the m⁵C modification in the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 mRNA 3′UTR region, leading to strengthened stability, thereby promoting LUSC progression (48). In CRC, YBX1 stabilized SKIL mRNA by m⁵C modification and increased SKIL expression. SKIL then facilitated the activation of transcriptional coactivator with PDZ-binding motif, thus accelerating tumor progression (41). Furthermore, YBX1 was shown to be increased in immune cells of tumor-bearing mice, elucidating the reason for m⁵C upregulation in CRC blood immune cells (49). This perspective suggests that YBX1 is not only involved in the m⁵C modification of tumor cells, but also influences the m⁵C modification of immune cells. Moreover, m⁵C-mediated RNA modification has also been shown to promote tumor metastasis. Tetraspanin 13 (TSPAN13) promoted acute myeloid leukemia stem cell migration/homing through the C-X-C motif chemokine (CXC)R4/CXCL12 pathway. In TET-mutant cells, YBX1 stabilized TSPAN13 mRNA via the m⁵C modification, thus enhancing migration/homing and cell self-renewal (43). Liu et al (50) also found that m⁵C-modified Orai calcium release-activated calcium modulator 2 promoted gastric cancer metastasis in a YBX1-dependent manner. In addition, YBX1 could stabilize leucine-rich repeat-containing 8 VRAC subunit A mRNA in an m⁵C-dependent manner to inhibit cervical cancer apoptosis (51).

m⁵C-mediated YBX1 functions in other diseases

Although YBX1 is mainly studied in cancers, it has also been demonstrated to regulate bone formation and metabolic diseases through m⁵C modification (52,53). Li et al (52) demonstrated that elevated YBX1 could facilitate osteogenesis and reduce bone loss. YBX1 deletion could repress the morphology of CD31-high, endomucin-high (CD31^highEMCN^high) endothelial cells, leading to decreased bone mass in an m⁵C-dependent manner. YBX1 could modulate the stability of EMCN, CD31 and bone morphogenetic protein 4 (BMP4), and influence the release of BMP4, thereby controlling bone formation (52). Furthermore, YBX1 could promote adipogenesis and autophagy in an m⁵C-dependent manner, thus leading to obesity (45). In a previous study it was found that YBX1 directly recognized m⁵C-modified Unc-51 like autophagy activating kinase 1 (ULK1) mRNA and improved its stability. In addition, YBX1 enhanced ULK1-mediated autophagy and increased obesity formation (53). These findings indicate that YBX1-mediated m⁵C modification assumes a crucial function in various diseases.

The dysregulation of YBX1-mediated RNA m⁵C modification represents a potential target for therapeutic strategy in human diseases. Regulating the relationship between YBX1 and m⁵C-modified transcripts holds promise for developing novel therapeutic strategies aimed at restoring normal RNA metabolism and cellular homeostasis. Furthermore, elucidating the mechanisms underlying YBX1-mediated m⁵C modification will advance our understanding of RNA biology and disease pathogenesis. Future investigations should concentrate on unraveling the spatiotemporal dynamics of YBX1-m⁵C co-actions and their function in different cellular microenvironments.

In conclusion, YBX1 plays a crucial role in modulating the RNA m⁵C modification, which is vital for controlling gene expression essential for cellular function and adaptation, especially in cancers and drug resistance (Fig. 2). Through its interactions with m⁵C methyltransferases, readers and RNA molecules, YBX1 influences various aspects of RNA metabolism and cellular physiology. Dysregulation of the YBX1-mediated m⁵C modification has implications for human health and disease, emphasizing its potential as a therapeutic target. Current research focuses on understanding the connection between YBX1 and the m⁵C modification, which will enhance our knowledge of RNA regulation and offer novel strategies for disease therapy.

Figure 2.

Functions of YBX1 in m⁵C RNA modification. m⁵C writers and erasers dynamically modulate m⁵C modification, catalyze and remove methylation, and ALYREF facilitates the export of m⁵C-tagged mRNA. YBX1 recognizes the m⁵C-modified mRNA in the cytoplasm, thus enhancing mRNA stability, thereby promoting tumor progression and resistance. YBX1, Y-box binding protein 1; m⁵C, 5-methylcytosine; ALYREF; Aly/Ref export factor; NSUN, NOP2/Sun RNA methyltransferase; TET1, ten-eleven translocation 1; DNMT2, DNA methyltransferase 2; ALKBH1, AlkB homolog 1.

4. YBX1 is a regulatory protein of RNA m⁶A modification

Mechanism of m⁶A modification

To date, the most extensively studied RNA modification is m⁶A. This modification involves the methylation of adenosine residues at position six of RNA by m⁶A methyltransferases (31). The m⁶A modification regulates various molecular events, including RNA stability, RNA transport, the splicing of pre-mRNA, transcription, post-transcription and translation (54–56). The m⁶A methylation is the most abundant modification of RNA, found in long ncRNA (57–62), circular RNAs (63,64), miRNAs (65,66), mRNA (58,67), and rRNA and mtRNA (68), modulating the fates of RNA and affecting a variety of biological processes including spermatogenesis (69), pluripotency of embryonic stem cells (70), cell differentiation (71), proliferation (72), tumor metastasis (73), drug resistance of cancer (74) and the metabolism of tumor cells (75).

During the m⁶A modification processes, a variety of enzymes and proteins are involved, including m⁶A methyltransferases (commonly referred to as ‘writers’), m⁶A demethylases (known as ‘erasers’) and m⁶A-recognized factors (called ‘readers’). The writers contain methyltransferase-like (METTL)3, METTL14, WT1 associated protein, METTL16 and RNA binding motif protein 15, which assume the catalysis of m⁶A in RNA (76–79). Notably, two proteins, AlkB homolog 5, RNA demethylase and FTO α-ketoglutarate-dependent dioxygenase, have been demonstrated to be capable of removing the m⁶A modification from RNA (80–83). Furthermore, YTHDF1-3, YTHDC1-2, heterogenous nuclear ribonucleoprotein A2/B1, heterogenous nuclear ribonucleoprotein A/Cand insulin-like growth factor 2 mRNA binding protein (IGF2BP)1-3 have been identified as factors that recognize and bind to m⁶A-modified RNA (80,84–91). Normally, methyltransferases and demethylases dynamically cooperate to regulate gene expression and determine the fate of molecules and cells (56). However, aberrant hypermethylation of m⁶A can lead to the development of multiple diseases, including cancers (92), intestinal inflammation (58) and liver disease (93).

m⁶A-regulated YBX1 functions

YBX1 can serve as a transcription factor or DNA-binding protein that regulates the expression of multiple genes (75). Accumulating evidence has revealed that YBX1 is a regulatory protein involved in the m⁶A modification. In 2021, Feng et al (15) demonstrated the significance of YBX1 in myeloid leukemia cell survival via m⁶A modification of BCL2 apoptosis regulator (BCL2). It was found that YBX1 was notably upregulated, promoting proliferation in myeloid leukemia cells. Mechanistically, YBX1 stabilized m⁶A-modified BCL2 and MYC proto-oncogene, BHLH transcription factor by cooperating with IGF2BP1 and IGF2BP3. Furthermore, the loss of YBX1 led to an accelerated decay of m⁶A-tagged BCL2 mRNA, suggesting that YBX1 can regulate BCL2 expression in an m⁶A-dependent manner, thus playing a critical role in the survival of myeloid leukemia cells (15). Similarly, YBX1 is required for the survival of leukemia stem cells (94). YBX1 was revealed to interact with the IGF2BP protein to enhance the stability of m⁶A-tagged tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) mRNA. YBX1 deficiency downregulated the expression of YWHAZ by promoting YWHAZ mRNA degradation in an m⁶A-dependent manner, thereby maintaining leukemia cell survival (94). Additionally, YBX1 has been shown to affect embryonic development (95,96) and ischemic stroke (97) in an m⁶A-dependent manner. YBX1 was found to influence the gene expression of zygotic genome activation by m⁶A-modified RNA, thereby regulating early embryonic development. YBX1 fine-tuned polycomb repressive complex 2 activity to regulate embryonic neural development (95) Peng et al (97) also observed that NSC-derived exosomes loaded with YBX1 inhibited neuronal pyroptosis, thereby mitigating the development of ischemic stroke. YBX1 interacted with IGF2BP1 to heighten the stability of m⁶A-tagged G protein-coupled receptor 30 (GPR30) mRNA, which increased the expression of GPR30. GPR30 then facilitated the degradation of NLRP3 by ubiquitination, alleviating the progression of ischemic stroke. The inhibition of IGF2BP1 decreased YBX1 binding to GPR30, which contributed to the progression of ischemic stroke (97). YBX1 is a regulatory protein involved in the m⁶A modification of RNA. It stabilizes the mRNA of target genes, thereby enhancing their expression. Unlike the YBX1 regulation model in the m⁵C modification, the IGF2BP protein is required for YBX1 to maintain mRNA stability in the m⁶A modification. Furthermore, YBX1 can function as an m⁶A reader, dependent on the IGF2BP protein (98–100). The functions of YBX1 in N1methyladenosine (m¹A) and 7methylguanosine (m⁷G) remain unknown. Therefore, further investigation is needed to explore the contributions and potential mechanisms of YBX1 in RNA methylation modifications.

The dysregulation of YBX1-mediated RNA m⁶A modification has emerged as a hallmark of numerous diseases, making it a potential target for therapeutic interventions (15,101–105). Targeting the interaction between YBX1 and m⁶A-modified transcripts holds promise for developing novel therapeutic approaches aimed at restoring normal RNA modification in diseased states. Furthermore, elucidating the mechanisms of the YBX1-mediated m⁶A modification will provide novel insights into the complex dynamics of RNA regulation. In addition, it is essential to uncover the roles of YBX1 in m⁶A modification and its effects on cellular processes and the development of diseases.

5. YBX1 inhibitor SU056 could reverse drug resistance

Research has shown that YBX1 upregulation could promote tumor development by regulating m⁵C and m⁶A modifications. SU056 is a small molecule of azopodophyllotoxin that inhibits YBX1, and helps reverse drug resistance and inhibit tumor development (17–20). YBX1 knockdown was shown to reduce gemcitabine resistance, and SU056 in combination with gemcitabine overcame gemcitabine resistance in pancreatic cancer (18). Additionally, SU056 was demonstrated to inhibit triple-negative breast cancer growth in preclinical models by targeting YB-1 to disrupt protein translation mechanisms (17). SU056 also reduced the progression of ovarian cancer while sensitizing to paclitaxel-mediated cytotoxicity (20). Furthermore, platinum-induced cell stress enhanced YBX1, which was expressed at high levels in platinum-resistant ovarian cancer. YBX1 recognized and stabilized CHD3 mRNA through m⁵C modification. By targeting YBX1, SU056 reversed platinum resistance and enhanced tumor cell killing (19). In addition, another YBX1 inhibitor, 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate, also exerted similar antitumor effects, although its mechanism of action remains unexplored (106). The activities and efficacy profiles of other YBX1 inhibitors also remain incompletely characterized.

Collectively, SU056 has been demonstrated to exert antitumor effects and reverse drug resistance by targeting YBX1, with its effectiveness dependent on the cellular expression of YBX1 (20). Additionally, YBX1 has been shown to facilitate tumor progression and confer drug resistance through its regulation of RNA m⁵C and m⁶A modifications (5,107–109). Therefore, it is hypothesized that the antitumor effect and reversal of drug resistance exerted by SU056 may be attributed to its inhibition of RNA m⁵A and m⁶A methylation.

6. Perspectives and conclusions

YBX1, a DNA/RNA-binding protein, is implicated in DNA repair, mRNA transcription, pre-mRNA splicing, mRNA stability regulation, translation and exosome sorting (28,110), influencing the development of multiple diseases. Notably, extensive evidence has shown that YBX1 plays multifunctional roles in cancer progression and drug resistance (111,112). Furthermore, RNA methylation modifications are dysregulated in cancers and serve as potential targets of tumor therapy (31). Although YBX1 is implicated in various cancer hallmarks, its underlying mechanisms, particularly those related to RNA methylation modifications during cancer development such as m¹A, m⁵C, m⁶A and m⁷G require further investigation. Understanding the functional role of YBX1 in RNA modifications could provide novel insights into the regulation of gene expression, cellular homeostasis and molecular pathogenesis. This knowledge may also lead to promising therapeutic strategies that target RNA modifications for cancer treatment.

Given its critical roles in cancer pathogenesis and treatment resistance, YBX1 has emerged as an attractive therapeutic target for anticancer therapy. Several approaches have been explored to modulate YBX1 activity, including the use of small molecule inhibitors. The YBX1 inhibitor SU056 has shown promising efficacy in inhibiting tumor growth, promoting cell apoptosis and sensitizing cancer cells to chemotherapy. Despite the significance of YBX1 in cancer, the clinical application of YBX1 inhibitors remains limited. Further investigations should focus on the regulatory networks between YBX1 and RNA modifications, which will broaden the understanding of the role of YBX1 in cellular activity and tumorigenesis.

In summary, YBX1 plays a pivotal role in regulating RNA modifications specifically m⁶A and m⁵C RNA modifications influencing a variety of cellular processes and diseases (Table I). Understanding the underlying mechanisms of YBX1 in RNA modification is crucial for developing effective strategies to treat cancers. Targeting YBX1 and RNA modifications may help overcome the challenges of drug resistance in the clinic, and the YBX1 inhibitor SU056 exhibits great potential as an antitumor agent.

Table I.

Main roles of YBX1 in disease through RNA-methylated modification.

Gene symbol	Type of enzyme	Disease type	Role	Main target	Modification	Expression	(Refs.)
YBX1	m5C reader	Colorectal cancer	Oncogene	SKIL	N/A	No change	(41)
		Ovarian cancer	Oncogene	E2F1	3′-UTR	Upregulated	(7)
		NSCLC	Oncogene	NRF2	5′UTR	Upregulated	(46)
		Endometrial cancer	Oncogene	SLC7A11	N/A	No change	(4)
		AML	Oncogene	TSPAN13	N/A	No change	(49)
		KIRP and CRC	Oncogene	N/A	N/A	Upregulated	(10,52)
		LUSC	Oncogene	PFKFB4	3′UTR	No change	(48)
		Pancreatic cancer	Oncogene	TIAM2	N/A	No change	(36)
		EGFR-mut NSCLC	Oncogene	QSOX1	CDS	Upregulated	(5)
		Gastric cancer	Oncogene	ORAI2	N/A	No change	(50)
		Cervical cancer	Oncogene	LRRC8A	N/A	No change	(51)
		ccRCC	Oncogene	PEBP1	3′UTR	No change	(11)
		Pancreatic cancer	Oncogene	Androgen receptor	5′ end	Upregulated	(37)
		Cervical cancer	Oncogene	KRT13	3′-UTR	No change	(45)
		Cholangiocarcinoma	Oncogene	IncRNA NKILA	N/A	No change	(61)
		Epithelial ovarian cancer	Oncogene	E2F5, YY1 and RCC2	N/A	No change	(47)
		Gastric cancer	Oncogene	FOXC2	N/A	No change	(62)
		UCB	Oncogene	HDGF	3′-UTR	Upregulated	(29)
		Osteoporosis	N/A	CD31, EMCN and BMP4	3′-UTR	Downregulated	(52)
		Obesity	N/A	ULK1	5′UTR	Upregulated	(53)
		MZT	NA	CAP1, TEX2 and TPP2	CDS	No change	(30)
YBX1	m6A	Ischemic stroke	N/A	GPR30	N/A	No change	(97)
		Embryo development	N/A	PRC2	N/A	No change	(96)
		CML	Oncogene	YWHAZ	N/A	Upregulated	(94)
		AML	Oncogene	MYC and BCL2	3′ UTR	Upregulated	(15)

YBX1, Y-box binding protein 1; m⁵C, 5-methylcytosine; SKIL, SKI like proto-oncogene; E2F1, E2F transcription factor 1; UTR, untranslated region; N/A, information not available; NSCLC, non-small cell lung cancer; NRF2, nuclear factor erythroid 2-related factor 2; SLC7A11, solute carrier family 7 member 11; AML, acute myeloid leukemia; TSPAN13, tetraspanin 13; KIRP, kidney renal papillary cell carcinoma; CRC, colorectal cancer; LUSC, lung squamous cell carcinoma; PFKFB4, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4; TIAM2, TIAM Rac1 associated GEF 2; QSOX1, quiescin sulfhydryl oxidase 1; ORAI2, calcium release-activated calcium modulator 2; LRRC8A, leucine-rich repeat-containing 8 VRAC subunit A; ccRCC, clear cell renal cell carcinoma; PEBP1, phosphatidylethanolamine binding protein 1; NKILA, NF-κB-interacting lncRNA; FOXC2, forkhead box C2; HDGF, heparin-binding growth factor; EMCN, endomucin; BMP4, bone morphogenetic protein 4; ULK1, Unc-51 like autophagy activating kinase 1; MZT, maternal-to-zygotic transition; m⁶A, N6-methyladenine; GPR30, G protein-coupled receptor 30; CML, chronic myeloid leukemia; YWHAZ, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta; BCL2, BCL2 apoptosis regulator; EGFR, epidermal growth factor receptor; KRT13, keratin 13; E2F5, E2F transcription factor 5; YY1, Yin Yang 1; RCC2, regulator of chromosome condensation 2; UCB, urothelial carcinoma of the bladder; CAP1, cyclase-associated protein 1; TEX2, testis expressed 2; TPP2, tripeptidyl peptidase 2; CDS, cold shock domain; PRC2, polycomb repressive complex 2; NA, not available.

Glossary

Abbreviations

Y-box

binding protein 1

m⁵C

5-methylcytosine

m⁶A

N6-methyladenine

CDS

cold shock domain

SKIL

SKI like proto-oncogene

NSCLC

non-small cell lung cancer

NRF2

nuclear factor erythroid 2-related factor 2

SLC7A11

solute carrier family 7 member 11

TSPAN13

tetraspanin 13

CRC

colorectal cancer

LUSC

lung squamous cell carcinoma

QSOX1

quiescin sulfhydryl oxidase 1

EMCN

endomucin

BMP4

bone morphogenetic protein 4

ULK1

Unc-51 like autophagy activating kinase 1

GPR30

G protein-coupled receptor 30

YWHAZ

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta

BCL2

BCL2 apoptosis regulator

Funding Statement

Funding: No funding was received.

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Authors' contributions

XX conceived and designed the review, as well as drafted and provided overall supervision of the manuscript. GX performed and contributed to specific sections of the review and participated in manuscript revision. YX was involved in revising the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

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Competing interests

The authors declare that they have no competing interests.