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Aberrant epigenetic regulation can alter cell fates and result in unrestrained cell growth, leading to cancer development. Understanding the complex epigenetic pathways may point the way for advanced cancer therapy. Several recent studies identified mutations in components of the chromatin modification machinery in different types of cancer 1-3. Interestingly, these mutations include two important enzymes which are involved in histone H3 lysine 27 (H3K27) methylation, EZH2 (H3K27 methyltransferase) and UTX (H3K27 demethylase), consistent with the fact that abnormal H3K27me3 levels can cause tumorigensis 4. Previous studies indicate that EZH2 is strongly involved in cancer progression 5-7. Two independent findings further show that UTX may control cell cycle progression through RB pathway 8, 9.
Wang et. al. started to investigate the role of UTX in transcriptional regulation by mapping UTX occupancy on human promoters in primary human fibroblasts, and found that the most significant network of genes bound by UTX is tied to cell cycle pathways centered on the tumor suppressor RB and RB binding proteins 8. This UTX occupancy pattern was observed in fibroblasts but not in embryonic stem cells, suggesting that UTX occupancy of RB pathway genes may regulate the capacity for proliferation and self-renewal. They further showed that UTX depletion causes increased H3K27me3 levels at UTX-occupied genes, decreased target mRNA levels, and increased S-phase entry to promote cell proliferation. Moreover, overexpression of UTX decreased cell proliferation in human primary fibroblasts in a manner dependent on its demethylase activity. Concomitant depletion of either RB or HBP1 reversed the cell cycle arrest 8. Interestingly, the same finding was discovered in a genetic screen for ectopic cell growth mutants in Drosophila 9. Herz et. al. identified dUTX mutants with growth advantage due to increased proliferation and only a catalytic functional dUTX is able to rescue the over-representation phenotype. Classic genetic approaches further demonstrated that dUTX is a Notch-antagonist and ectopic Notch activation in dUTX mutant cells leads to tumor-like growth in an RB-dependent manner 9. Similar to Drosophila, the UTX-RB pathway is also evolutionary conserved in C. elegans, another model organism. Worm UTX-1 functions with RB and RB interacting proteins in vulva development in which they control the differentiation of equipotent vulva precursor cells 8. Taken together, these results uncover ancestral UTX regulation of RB and RB-binding proteins in vitro and in vivo, and UTX can affect cell proliferation as well as cell fate decision.
Alterations of expression in UTX and UTX-bound target genes are commonly seen in human cancers, as cancer cells are extremely versatile in the ability to adapt to different cellular and environmental conditions. Indeed, coordinate repression of UTX and the 49 UTX-occupied RB gene networks are enriched in cancers relative to their normal counterparts in a compendium of 1973 microarrays, comprised of 22 human tumors and their normal counterparts 8. Therefore, inactivation of UTX may be linked to transcriptional silencing of the RB pathway; moreover, the prognostic significance of UTX for cancer progression is conditional on EZH2 levels 8. Interestingly, another H3K27 demethylase JMJD3 is also a tumor suppressor gene, but it has a different role in controlling cell proliferation. JMJD3, but not UTX, is induced by RAS and activates the INK4A-ARF locus in response to oncogene and stress-induced senescence 10, 11. These results suggest that excess H3K27 methylase EZH2 and lack of H3K27 demethylase may be able to dysregulate H2K27me3 levels in cancers.
Mammalian UTX is also a component of MLL2/3 H3K4 methyltransferae complexes which is also implicated in cancer 12. Drosophila dUTX mutants have increased global H3K27me3 and reduced H3K4me1 levels, implying dUTX may function with MLL complex in vivo 9. Interestingly, aside from MLL2, UTX and another H3K4 demethylase JARIDIC were two novel mutations identified in clear cell renal cell carcinoma, suggesting H3K4 methylation status is also important in cancer 2. However, although the majority of UTX target genes are transcriptionally active, a specific set of UTX-occupied genes (e.g. olfactory receptors) lack of H3K4 methylation in human fibroblasts 8. Therefore, it is still unclear whether the UTX targeting mechanism is MLL dependent. UTX does not simply occupy genes with all H3K4 or H3K27 methylation 8, but composes a dynamic and independent layer of epigenetic regulation. It may also suggest that genetic mutation of UTX leads to epigenetic alternations which appear on a genome-wide scale. In sum, it has been proposed that UTX demethylates H3K27me3 at the promoters of genes encoding RB complex subunits to enable their coordinate transcription and thereby control G1 and S phase transition whereby affects cancer development (Fig 1). This is an exciting discovery of unanticipated role of UTX in cell cycle control and more detailed insights into the functional mechanism of UTX may pave the road towards better cancer therapy.
Supported by grants from California Institute for Regenerative Medicine (RN1-00529-1), National Cancer Institute (R01-CA118750), and American Cancer Society (RSG 07-084-01-MGO). H.Y.C. is an Early Career Scientist of the Howard Hughes Medical Institute.