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. Author manuscript; available in PMC: 2019 Jun 23.
Published in final edited form as: Cancer Cell. 2019 Feb 11;35(2):168–176. doi: 10.1016/j.ccell.2019.01.001

UTX Mutations in Human Cancer

Lu Wang 1, Ali Shilatifard 1,*
PMCID: PMC6589339  NIHMSID: NIHMS1036234  PMID: 30753822

Abstract

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear. Here, we discuss catalytic-dependent and -independent functions of UTX and its partners MLL3 and MLL4 as part of the COMPASS family during development and in oncogenesis.

Catalytic-Dependent and -Independent Functions of UTX

Discovery of UTX

The ubiquitously transcribed tetratricopeptide repeat gene on the Y chromosome (UTY) gene was first identified in mice and described to encode a tetratricopeptide repeat (TPR) protein. UTY is widely expressed in different tissues. The UTY protein contains an H-Y epitope, which is responsible for the rejection of male tissue by genotypically identical female tissue (Greenfield et al., 1996). In a UTY-negative cell line, the epitopes of H-YAb and H-YDb were found to be lost (Greenfield et al., 1996; King et al., 1994). As the name implied, both the human and the mouse UTY genes (UTY) are located on the Y chromosome. The ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (UTX) is a paralog of UTY that is encoded by KDM6A located on the X chromosome (Figure 1A). The UTX and UTY proteins have similar TPRs at their N termini. TPR domains can mediate protein-protein interactions (Smith et al., 1995). The C terminus of UTX contains a Jumonji C (JmjC) domain (Clissold and Ponting, 2001) that is most similar to UTY and JMJD3 (encoded by KDM6B) JmjC proteins (Shpargel et al., 2012) (Figure 1B). Unlike UTY, UTX causes no immune stimulation even though they share 83% sequence similarity (Figure 1C).

Figure 1. Human UTX and UTY.

Figure 1

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(A) Chromosomal localization of KDM6A, UTY, and KDM6B.

(B) Domain organization of human UTX and UTY proteins. The similarity (aligned score) for the tetratricopeptide repeats (TPR) domain and the Jumonji C (JmjC) domain of UTX and UTY was calculated by ClustalW sequence alignment.

(C) The aligned score for similarity between UTX, UTY, and JMJD3 was calculated by ClustalW sequence alignment.

UTX: A Histone H3K27 Demethylase

In 2007, a cluster of studies identified UTX as a histone H3K27 demethylase, which uncovered the function of UTX in transcriptional regulation (Agger et al., 2007; Hong et al., 2007; Lan et al., 2007; Lee et al., 2007; Smith et al., 2008). Recombinant UTX has a specific demethylation activity toward tri- and di-methyl H3K27 without affecting methylation on other histone lysine residues, such as H3K4, H3K9, H3K36, H3K79, and H4K20, in vitro (Lee et al., 2007). Point mutations (H1146A and E1148A) within the Fe(II)-binding motif of the catalytic JmjC domain of UTX abrogated its enzymatic activity (Figure 2) (Sengoku and Yokoyama, 2011; Walport et al., 2014), while deleting the N-terminal TPR domain also significantly reduced its catalytic activity (Lee et al., 2007). UTX was further found to control the H3K27 methylation level at the HOX gene clusters in different cell lines (Agger et al., 2007; Lan et al., 2007). In animals, loss of UTX was found to lead to the improper development of the posterior trunk in zebrafish (Lan et al., 2007) and a gonadal development defect in the nematode C. elegans (Agger et al., 2007).

Figure 2. Crystal Structure of the Catalytic Domain of UTX and UTY Proteins.

Figure 2

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(A) The catalytic fragment of UTX bound with histone H3K27me3 peptide, N-oxyalylglycine, and Ni (II), modified from PDB: 3AVR (Sengoku and Yokoyama, 2011).

(B) The crystal structure of JmjC domain of human UTY, modified from PDB: 3ZLI (Walport et al., 2014).

In human cell lines, depletion of UTX resulted in an increased level of di- and tri-methyl H3K27 at the HOX gene clusters, which further leads to the silencing of HOX genes (Lee et al., 2007). In induced pluripotent stem cells (iPSCs), UTX was demonstrated to directly partner with Oct4, Sox2, and KIF4 reprogramming factors and use its histone demethylase catalytic activity to facilitate iPSC formation. Kdm6a∆/Y iPSC formation could be rescued by overexpressing wild-type, but not catalytically dead (H1146A) UTX (Mansour et al., 2012), indicating that UTX functions through its catalytic activity, at least in iPSCs.

Although UTY and UTX share high sequence similarity, UTY was initially reported to lack detectable histone demethylase activity in vitro (Hong et al., 2007). However, a more detailed examination found that UTY has a significant but more limited H3K27 demethylase activity compared with UTX (around 2.6% of UTX levels) in vitro (Walport et al., 2014). Furthermore, the catalytic activity of UTY can be restored to UTX levels by a single P1214I mutation that promotes substrate binding. It will be very interesting to further characterize the in vivo significance of this attenuated catalytic activity of UTY, especially in UTX mutant cell lines or animals.

Catalytic-Independent Functions of UTX

Studies in C. elegans found that expression of catalytically inactive UTX did not rescue the wild-type level of tri-methylated H3K27 (H3K27me3) in UTX-deficient animals, which is consistent with the H3K27 demethylase function of UTX in other species. However, worms with catalytically dead UTX are fertile and able to produce viable progeny (Vandamme et al., 2012), demonstrating that the demethylase activity of UTX is not essential for either development or viability of C. elegans.

Using a model of mouse embryonic stem cell differentiation, UTX was found to contribute to mesoderm formation independently of H3K27 demethylase activity (Wang et al., 2012). Kdm6a homozygous mutant females had severe phenotypes mid-gestation, with developmental delay, neural tube closure, yolk sac, and heart defects. In contrast, hemizygous Kdm6a mutant male mice were runted at birth, with a small number surviving to adulthood due to the presence of the remaining paralog UTY. Since UTY has significantly less demethylase activity compared with UTX, these in vivo findings indicate critical catalytic-independent functions of UTX (Shpargel et al., 2012). However, how the UTX or UTY regulates gene expression in a catalytically independent manner remains unknown. One possibility is that UTX may function as a scaffold protein that facilitates the binding of other factors that directly regulate transcription. It will therefore be very interesting to compare cell lines or animals that are completely absent of UTX with those expressing catalytically dead UTX to see how UTX regulates gene expression and development in the presence and absence of its catalytic activity.

UTX Interactome and Functions of UTX-Associated Proteins

SPT6 and RNA Polymerase II

SPT6 (encoded by SUPT6H in human and by Supt6 in mice) is involved in the maintenance of chromatin structure during RNA polymerase II (Pol II) transcription elongation by interacting with and destabilizing histone dimer-tetramer nucleosomal contacts (Belotserkovskaya and Reinberg, 2004). In addition, these histone chaperones participate in histone reassembly by collecting and repositioning displaced free histones onto transcribed DNA regions after passage of Pol II (Bortvin and Winston, 1996; Saunders et al., 2003). In Drosophila, UTX was suggested to function in transcription elongation due to its being recruited to heat shock loci upon heat shock and associating with RNA Pol II (Smith et al., 2008). Depletion of UTX led to elevation of H3K27me3 levels and silencing of gene expression in Drosophila (Herz et al., 2010). In mammalian cells, SPT6 was found to directly interact with UTX and Pol II, and chromatin immunoprecipitation sequencing studies revealed an extensive genome-wide overlap of SPT6, Pol II, and UTX binding sites at transcribed regions that are devoid of H3K27me3 (Wang et al., 2013). Together, these studies indicated that UTX contributes to transcription directly (Figure 3A). Interestingly, another major H3K27 demethylase, JMJD3, was also found to interact with SPT6 and to activate transcription of bivalent genes (marked by both H3K4me3 and H3K27me3) by demethylating H3K27me3 and promoting transcriptional elongation (Chen et al., 2012). The molecular relationship between UTX and JMJD3, including whether they interact with SPT6 at the same or distinct chromatin loci, requires further investigation.

Figure 3. UTX Functions within an SPT6 Complex and the MLL3/4 COMPASS Family.

Figure 3

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(A) SPT6 enhances transcriptional elongation by tethering UTX to elongating RNA polymerase II (Pol II). Shown with SPT6, Pol II, and UTX are SETD2, the H3K36 methyltransferase that also interacts with elongating Pol II, and P-TEFb-containing super elongation complex (SEC).

(B) UTX associates with and functions in the MLL3/MLL4 COMPASS family, and these complexes implementing H3K4me1 and demethylating H3K27me3 are essential for enhancer activity.

(C) Size-exclusion chromatography of nuclear extract from HEK293T cells probed for UTX and components of the COMPASS family, suggesting that UTX may participate in non-COMPASS complexes.

MLL3 and MLL4 Associate with UTX within COMPASS

The human KMT2D (MLL4) cDNA was originally cloned from a cDNA library of the leukemia cell line K562, and was observed to be a homolog of ALL1 (MLL) (Prasad et al., 1997). MLL3 was subsequently identified as a paralog of MLL4 (Tan and Chow, 2001). UTX was first observed as a component of the MLL4 COMPASS in human leukemia cell line K562 cells (Issaeva et al., 2007). The association between UTX and PTIP with the MLL4 COMPASS complex was then demonstrated by immunoprecipitation and mass spectrometry. The interaction was further confirmed by PTIP affinity purification in HeLa cells (Cho et al., 2007), and similar components within the stable complex were observed (Figure 3B).

Genome-wide analysis demonstrated that Trr (orthologous to MLL3/MLL4 in Drosophila) is required to maintain the monomethylated H3K4 (H3K4me1) and acetylated H3K27 (H3K27ac) chromatin signature found at enhancers (Herz et al., 2012). Drosophila Trr primarily implements mono- and di-methylation of histone H3K4, a property conserved with mammalian MLL3 and MLL4 (Herz et al., 2012). Trr, MLL3, and MLL4 occupy enhancers and are required for enhancer activity (Dorighi et al., 2017; Herz et al., 2012; Hu et al., 2013; Rickels and Shilatifard, 2018). UTX was demonstrated to directly bind near the C terminus of MLL3/MLL4 (Kim et al., 2014), which indicates that UTX may regulate the catalytic activity of MLL3/MLL4. In support of this observation, both in Drosophila and mammalian cells, loss of UTX leads to a remarkable reduction of H3K4me1 and H3K27ac levels at enhancers (Herz et al., 2012; Wang et al., 2017). Recently, we found that UTX may be a component of complexes other than MLL3/MLL4 COMPASS. Using size-exclusion chromatography, we found that UTX and MLL3 only co-elute in a subset of fractions, with approximately 70% of UTX protein being found in smaller complexes in human breast cancer cell line CAL51 cells (Wang et al., 2018), and also a remarkable portion of UTX protein being found in smaller complexes in HEK293T cells (Figure 3C). Whether these are SPT6 or other, as yet to be identified, complexes will be an important area of future investigation that could help elucidate UTX functions in development and oncogenesis.

The UTX-MLL3/MLL4 complexes were also found to co-purify with estrogen receptor (ER) and retinoic acid receptor (RAR) upon ligand treatments (Rocha-Viegas et al., 2014; Xie et al., 2017). Although whether UTX interacts with ER or RAR directly, or depends on MLL3 or MLL4, remains unclear, these studies have shed light on the ligand-dependent transcriptional regulation controlled by histone H3K27 methylation, and suggest that specific histone methyltransferase inhibitors targeting H3K27 methylation can be used in cancer therapy.

Mutations of UTX and Its Associated Factors in Human Diseases

UTX Is a Highly Mutated Tumor Suppressor

UTX was first reported as a highly mutated histone H3K27 demethylase in a survey of different human cancers and cancer cell lines including acute myeloid leukemia, bladder carcinoma, breast cancer, chronic myeloid leukemia, colorectal adenocarcinoma, endometrial adenocarcinoma, and glioblastoma (van Haaften et al., 2009). Although both UTX and UTY have similar sizes, KDM6A appears to be much more frequently mutated in different cancers than UTY (Figure 4A). Furthermore, reintroduction of wild-type UTX into cancer cells bearing inactivating KDM6A mutations resulted in slowing of proliferation and marked transcriptional changes. KDM6A is also frequently mutated in human clear cell renal cell carcinoma (ccRCC) (Dalgliesh et al., 2010), which is the most common form of adult kidney cancer (Rini et al., 2009). Exon sequencing identified KDM6A as one of the most frequently mutated genes in ccRCC samples. In 101 cases of patient samples, 12 samples contained KDM6A mutations. Other studies provided additional evidence that KDM6A was highly mutated in different human solid tumors and leukemias (Bailey et al., 2018; Kandoth et al., 2013), including acute lymphoblastic leukemia (Mar et al., 2012), chronic myelomonocytic leukemia (Jankowska et al., 2011), bladder cancer (Nickerson et al., 2014), medulloblastoma (Robinson et al., 2012), prostate cancer (Grasso et al., 2012), and renal carcinoma (Dalgliesh et al., 2010) (Figure 4B).

Figure 4. UTX Mutations in Human Cancers.

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(A) Distribution of all KDM6A mutations that occur within the UTX protein coding region and UTY mutations that occur within the UTY protein coding region from cBioPortal. The red, green, and blue boxes indicate computationally identified TPR motifs while the yellow box indicates the JmjC domain.

(B) KDM6A mutation frequencies across various human cancer types as obtained from cBioPortal.

Mechanistic insight into UTX function as a tumor suppressor comes from Drosophila, where loss-of-function mutations within UTX led to increased H3K27 methylation levels and a growth advantage of UTX mutant cells in a Notch-dependent manner (Herz et al., 2010). In human breast cancer, UTX was found to be a central factor in mediating epithelial-mesenchymal transition (EMT). Depletion of UTX in invasive breast cancer cell lines led to increased Myc-dependent expression of EMT factors, such as SNAI and ZEB1/2 (Choi et al., 2015). In human fibroblast cells, UTX was found to regulate many RB-binding proteins, the expression of which are coordinately decreased in human cancers. Overexpressing the wild-type UTX in primary human fibroblast cells was sufficient to induce cell-cycle arrest (Wang et al., 2010). In human pancreatic cancers, depletion of UTX or mutations within UTX led to elevated TP63 expression, which is believed to be one the major drivers of pancreatic cancer (Andricovich et al., 2018).

In human T cell acute lymphoblastic leukemia (T-ALL), UTX functions as a tumor suppressor and is frequently genetically inactivated in T-ALL. Depletion of UTX by short hairpin RNA (shRNA) accelerated the initiation and progression of T cell leukemia in a NOTCH1-overexpressing T-ALL model (Ntziachristos et al., 2014). Interestingly, in human T-ALL, UTX functions as a frequently inactivated tumor suppressor, while JMJD3, another H3K27 demethylase, controls important oncogenic gene targets and is essential for the initiation and maintenance of the T-ALL cells. The differing functions of UTX and JMJD3 may be due to the lack of the N-terminal TPR domain in the JMJD3 protein. The different mechanisms of chromatin recruitment for UTX/UTY and JMJD3 remain to be investigated.

To date, it is still unclear why the loss of UTX activates these oncogenes. One possibility is that loss of UTX function could lead to DNA damage (Akdemir et al., 2014; Hofstetter et al., 2016; Zhang et al., 2013). Although UTY is found to be much less frequently mutated in human cancers compared with KDM6A (Li et al., 2018), we are still able to observe UTY mutations within the catalytic domain-coding region in multiple human cancers, such as cutaneous melanoma (P1091L), bladder urothelial carcinoma (D1119N), B cell lymphoma (N1134K), small cell lung cancer (L1144V), oligodendroglioma (V1152A), chondroblastic osteosarcoma, and cutaneous melanoma (G1170S) (Figure 4B). It will be essential to determine whether these mutations in UTY are inactivating or if they could increase its catalytic activity of the enzyme, as was seen with the experimentally introduced P1214I mutation (Walport et al., 2014).

Mutations in UTX-Associated Factors

Multiple UTX-associated proteins are dysregulated in human cancers, including PTIP (Ray Chaudhuri et al., 2016), RBBP5 (Alvarado et al., 2017), and ASH2L (Butler et al., 2017). MLL3 and MLL4 components of COMPASS are the only lysine methyltransferases associated with UTX, and they are among the most frequently mutated genes in human cancers (Biankin et al., 2012; Chen et al., 2014; Ellis et al., 2012; Fujimoto et al., 2012; Gui et al., 2011; Li et al., 2013; Lin et al., 2014; Okosun et al., 2014; Saigo et al., 2008; Song et al., 2014; Wang et al., 2011; Zang et al., 2012). MLL3 and MLL4 each have multiple plant homeodomain (PHD) fingers in their N terminus and a typical SET domain in the C terminus, which is responsible for histone H3 lysine 4 methyltransferase activity (Hu et al., 2013). We recently identified two mutation hotspots within the PHD fingers of the MLL3 protein. Mutations within the MLL3 PHD domains abolish the interaction between the BAP1 tumor suppressor complex and MLL3-UTX, which leads to attenuation of enhancer activity. Although both MLL3 and MLL4 catalyze enhancer H3K4 mono-methylation (Herz et al., 2012; Lee et al., 2013; Sze and Shilatifard, 2016), the SET domain of MLL4 but not MLL3 is found to be highly mutated in human lymphoma. Studies performed by the Pasqualucci (Zhang et al., 2015) and Wendel groups (Ortega-Molina et al., 2015) demonstrated that missense or nonsense mutations within the MLL4 protein lead to the degradation of MLL4 COMPASS both in vitro and in vivo. Loss of MLL4 by shRNA knockdown or CRISPR knockout significantly accelerated lymphoma development in animals. These results are consistent with UTX participating in multiple tumor suppressive complexes (Figure 5). Any mutations within UTX that disrupt the interaction between UTX and these factors may also affect the proper function of these complexes and thus contribute to tumorigenesis. In addition, it would be interesting to determine to what extent mutation of UTX and MLL3/MLL4 are mutually exclusive in all human tumor tissues as they are in bladder cancer (Meeks and Shilatifard, 2017). This will help clarify whether the function of UTX in human cancers is related to its participation in MLL3/MLL4 COMPASS and/or other complexes (Figure 3C).

Figure 5. Mutations in UTX-Associated MLL3/MLL4 COMPASS Family.

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In normal cells, the UTX/MLL3 COMPASS complex is recruited by tumor-suppressive factors, such as BAP1 complex to enhancers, and controls the expression of multiple tumor suppressors (Wang et al., 2018). In tumor cells, mutations occurring in the MLL3-PHD domain lead to dissociation between UTX/MLL3 COMPASS and BAP1 complex (left). UTX mutations (right) that disrupt the interaction between UTX and COMPASS may also affect the proper function of these complexes and thus contribute to tumorigenesis.

Targeting UTX Mutant Cancer Cells

Methylation of lysine 27 on histone H3 by EZH2 within the polycomb repressive complex 2 (PRC2) proteins is associated with gene silencing in many developmental processes (Kuzmichev et al., 2002; Margueron and Reinberg, 2011; Swigut and Wysocka, 2007). As a histone H3K27me2/3 demethylase, loss of UTX leads to the increased global or locus-specific level of H3K27 methylation in different species (Lan et al., 2007; Maures et al., 2011; Miller et al., 2010; Schuettengruber et al., 2017; Seenundun et al., 2010; Smith et al., 2008). In human cancers, depletion of UTX or loss-of-function mutations of UTX also links H3K27me3 to gene expression. The imbalance between UTX and PRC2 function has been observed in numerous human cancers due to loss-of-function mutations within UTX or gain-of-function mutations within EZH2 (Wang et al., 2018) (Figure 6). In bladder carcinoma, loss of UTX results in aberrant activation of PRC2-regulated transcription repression and further creates an EZH2 dependency in cell proliferation (Fantini et al., 2018). Cells without UTX demonstrate higher levels of H3K27me3 by western blot analysis, and are more sensitive to EZH2 inhibitor treatments (Ler et al., 2017). Interestingly, in human multiple myeloma (MM), loss of UTX does not affect global H3K27me3 levels, but UTX mutant MM cells are sensitized to EZH2 inhibitors (Ezponda et al., 2017). In a mouse model of lung cancer, small-scale in vivo CRIPSR library screening identified UTX as a key regulator in lung cancer progression, with loss of UTX leading to increased H3K27me3 levels, in part due to increased EZH2 expression (Wu et al., 2018). Treatment with EZH2 inhibitors preferentially suppressed the growth of UTX-deficient lung tumors in vivo. In UTX deficiency-induced pancreatic cancer, tumor cells were more sensitive to BET inhibitor treatment due to loss of the aberrantly active enhancers for genes encoding transcription factors that drive squamous and quasi-mesenchymal differentiation (Andricovich et al., 2018). However, mechanistic details of how loss of UTX stimulates enhancer activation are lacking. As UTX contains both catalytic and non-catalytic functions, it would be more efficient to target both functions of UTX for cancer treatment. On the other hand, although UTX functions as a tumor suppressor in multiple human cancers, global inhibition of the H3K27 demethylase family by small-molecule inhibitors, such as GSKJ4, would also affect maintenance of the disease, especially when the tumor cells have high levels of JMJD3 and decreased UTX.

Figure 6. Balance between Functional UTX and PRC2 as a Targeted Therapy for Human Cancer.

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Balance between UTX/COMPASS and PRC2 complexes in the setting of histone H3 lysine 27 methylation levels (top). Inactivating mutations of UTX or gain-of-function EZH2 mutations result in an oncogenic advantage for PRC2 (bottom). Resetting the epigenetic balance by targeting the polycomb complex or stabilizing UTX and its associated factors could be a strategy for treating human cancers resulting from UTX/COMPASS or PRC2 mutations.

Future Directions

Although the UTX gene, KDM6A, was identified over 20 years ago, increased interest in UTX biology in recent years derives from it being one of the most frequently mutated histone modifiers in different human cancer types, with the vast majority of UTX mutations being loss-of-function mutations (van Haaften et al., 2009). However, to date, several important questions remain to be addressed to fully elucidate UTX function in human cancers. First, according to structural analysis, UTX does not possess a DNA binding domain, raising the question of how UTX is recruited to enhancer chromatin. One possible mechanism is that UTX-associated proteins such as MLL3/MLL4 COMPASS subunits recruit UTX to enhancer loci. However, because depletion of both MLL3/MLL4 will affect enhancer activity and result in destabilization of UTX protein, it is difficult to determine whether MLL3 and MLL4 recruit UTX or just stabilize it. Second, as reported by different groups, loss of UTX leads to the decrease of enhancer H3K4 mono-methylation, which is mainly catalyzed by the MLL3/MLL4 COMPASS family, but how UTX affects MLL3/MLL4 COMPASS activity remains unclear. Third, it will be important to investigate which signaling pathways mediate the stability of UTX in human cancers. Since the majority of somatic mutations of KDM6A in patients are heterozygous mutations, pharmacological stabilization of the remaining wild-type UTX may be a potential therapy (Liang et al., 2017). Lastly, because the other UTX family members such as JMJD3 may function as an oncogenic H3K27 demethylase, it is essential to consider the different cellular functions of JMJD3 and UTX/UTY when considering therapeutic targeting of their highly related enzymatic domains.

ACKNOWLEDGMENTS

We are grateful Dr. Edwin Smith for critical reading of the manuscript and Laura Shilatifard for editorial assistance. We apologize to colleagues whose studies were not cited in this review due to space limitations. Studies in the Shilatifard laboratory are supported by the NIH (R35CA197569).

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