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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cell Cycle. Author manuscript; available in PMC Aug 15, 2010.
Published in final edited form as:
Published online Aug 15, 2009.
PMCID: PMC2846299
NIHMSID: NIHMS185710

The tumor suppressor microRNA-101 becomes an epigenetic player by targeting the Polycomb group protein EZH2 in cancer

The Polycomb group protein (PcG) enhancer of zest homologue 2 (EZH2) is overexpressed in several cancers although the precise mechanism had not been demonstrated.1 Now there is strong evidence that microRNA-101 (miR-101) downregulation in cancer is a major cause of aberrant overexpression of EZH2, leading to epigenetic reprogramming of terminally differentiated cells back to the de-differentiated, proliferative cancer state (Fig. 1).2, 3

Figure 1
In normal cells miR-101 is expressed and binds to target sites in the 3′ untranslated region of the mRNA of EZH2 via the RNA induced silencing complex (RISC), leading to translational repression and/or mRNA destabilization. Normal EZH2 levels ...

PcG proteins were discovered as homeotic regulators that establish epigenetic patterns, affect stem cell maintenance, development, imprinting, X-inactivation, and have been implicated in tumorigenesis.4 EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), which trimethylates lysine 27 of histone H3 (H3K27me3). The H3K27me3 mark is recognized and bound by the Polycomb Repressive Complex 1, leading to gene repression by a poorly understood mechanism that involves histone modifications, recruitment of chromatin binding proteins such as heterochromatin binding protein 1, and chromatin compaction.4

EZH2 overexpression promotes carcinogenesis, enhances proliferation, and is significantly associated with metastases in prostate and breast cancer.1 In cancer cells, in addition to canonical PRC2, there are non-canonical PRC2s that function abnormally and possibly arise due to the differential PRC2 subunit stoichiometry found in a neoplastic cell.5 Aberrantly high levels of EZH2 directly cause de novo silencing of genes, which contributes to the significant epigenetic reprogramming seen in cancer (Fig. 1).6, 7

A significant subset of PRC2 target genes in cancer were also PRC2 target genes in ES cells 8 and PRC2-mediated H3K27me3 of tumor suppressor and pro-differentiation genes in stem cells may predispose the gene to aberrant permanent silencing in cancer.9 Possible therapeutic approaches to counter the extensive involvement of EZH2 in cancer progression have been explored pharmacologically 10 and our recent discovery that miR-101 directly targets EZH2 creates a greater impetus to develop microRNA (miRNA)-based therapeutics for human disease.2

miRNAs are ~20–22 nucleotide non-coding RNA molecules that tend to negatively regulate genes by binding to the 3′ untranslated region of the target mRNA via the RNA-induced silencing complex causing mRNA destabilization and/or translational inhibition. miRNAs have been implicated in numerous critical biochemical processes and the aberrant expression of miRNAs disrupts normal cellular functions causing morbidity, including neurological, cardiovascular, and neoplastic disease.11

We conducted molecular profiling of transitional cell carcinomas of the bladder (TCC) and found extensive miRNA misexpression between tumors and matched normal tissues.2 Functional studies showed that a miRNA that was downregulated in the tumors, miR-101, significantly inhibited cell proliferation and colony formation in TCC cell lines. miR-101 transfection dramatically repressed EZH2 expression and luciferase assays showed that miR-101 binds to the 3′UTR of EZH2 in a sequence dependent manner. TCC cells treated with either shRNA or siRNA to EZH2 showed the same phenotype as re-expression of miR-101, indicating that the primary function of miR-101 in TCC is to inhibit EZH2 (Fig. 1). An analysis of recent miRNA profiling studies in cancer revealed that miR-101 was downregulated in breast, lung, prostate, ovarian, colon, and liver cancers,12 which suggests that decreased miR-101 expression may be a marker of solid tumors.2, 3

Intriguingly, miR-101 can be produced from two genomic loci, miR-101-1 on chromosome 1p31 and miR-101-2 on chromosome 9p24. This complicates attempts to address the transcriptional regulation of miR-101, although loss of heterozygosity at chromosome 1p and chromosome 9p are associated with cancer. In fact, a recent report convincingly showed that genomic loss of miR-101 occurs in a significant number of prostate tumors and was associated with progression.3 Further studies will have to examine the causes of miR-101 downregulation in tumors without LOH at either miR-101 locus. However, it seems clear that the resulting upregulation of miR-101 targets, including EZH2, by decreases in miR-101 is selected for during tumorigenesis. Interestingly, miR-101 is repressed in human embryonic stem (ES) cells, but is upregulated during differentiation, which links the proliferative, de-differentiated states of cancer and stem cells by a common miRNA.13

References

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