Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer

Abstract

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and that regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here, we show that the expression and function of EZH2 in cancer cell lines is inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancers (6/16) and 66.7% of metastatic disease (22/33). We propose that genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.Polycomb Group Proteins, including EZH2, play a master regulatory role in controlling important cellular process such as maintaining stem cell pluripotency (1-3), cell proliferation (4,5), early embryogenesis (6), and X chromosome inactivation (7). EZH2 functions in a multiprotein complex called Polycomb Repressive Complex 2 (PRC2) which includes SUZ12 (Suppressor of Zeste 12) and EED (Embryonic Ectoderm Development) (8,9). The primary activity of the EZH2 protein complex is to tri-methylate histone H3 lysine 27 (H3K27) at target gene promoters, leading to epigenetic silencing (10,11). Mounting evidence suggests that #Address correspondence and requests for reprints to:

Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

“…The protumorigenic and prometastatic miRNA miR-19b was upregulated in metastatic cells (Table 2), whereas the antimetastatic miR-16 was downregulated in lung metastatic cells (Table 3) (Hurst et al, 2009). However, there were few exceptions: metastatic cells expressed elevated levels of miR-101, which has been described as tumor suppressor in other cancer types (Varambally et al, 2008). In summary, we have described results that suggest a role for miRNAs in changing the protein expression pattern in cancer cells depending on the site of metastasis.…”

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…In addition, H3K27 methylation has been shown to mark genes for de novo methylation in cancer (Schlesinger et al, 2007). A recent study found that frequent overexpression of EZH2 in aggressive solid tumors is largely due to the loss of its regulator microRNA-101 (Varambally et al, 2008). More specifically, reintroduction of miR-101 or knockdown of EZH2 expression was sufficient to reduce H3K27 trimethylation and increase RUNX3 mRNA levels.…”

The microRNA network and tumor metastasis

“…miR-148 repressed expression of DNMT3B through binding with high homology to the region of the coding sequence of the DNMT3B transcript, but the mechanism remained unclear. In contrast to miR-148a, miR-101 modulates cancer epigenetics by repressing the polycomb group protein EZH2, which contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells (Varambally et al, 2008;Friedman et al, 2009). Not only does miR-101 suppress the expression and function of EZH2 in cancer cell lines but also there is an inverse correlation between miR-101 expression and EZH2 expression during cancer progression in human prostate tumors (Varambally et al, 2008).…”

“…In contrast to miR-148a, miR-101 modulates cancer epigenetics by repressing the polycomb group protein EZH2, which contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells (Varambally et al, 2008;Friedman et al, 2009). Not only does miR-101 suppress the expression and function of EZH2 in cancer cell lines but also there is an inverse correlation between miR-101 expression and EZH2 expression during cancer progression in human prostate tumors (Varambally et al, 2008). Varambally et al (2008) found that loss of one or the other of the two genomic loci of miR-101 occurred more frequently in metastatic tumor cells.…”

“…Not only does miR-101 suppress the expression and function of EZH2 in cancer cell lines but also there is an inverse correlation between miR-101 expression and EZH2 expression during cancer progression in human prostate tumors (Varambally et al, 2008). Varambally et al (2008) found that loss of one or the other of the two genomic loci of miR-101 occurred more frequently in metastatic tumor cells. Therefore, the genomic loss leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression and metastasis.…”