![]() ![]() Similarly, the expression levels of these 63 miRNAs were downregulated in breast cancer cells BT-549 and SKBr3 compared to breast benign epithelial cells H16N2 and HME ( Fig. We found 63 miRNAs that were downregulated in DU145 cells compared to the normal cell lines, and inhibition of EZH2 by knockdown restored expression of these miRNAs ( Fig. We primarily observed miRNAs that were decreased in cancer cells relative to benign that are targets of repression by EZH2, and thus PRC2. In parallel, we compared these miRNA profiles with DU145 cells relative to four benign epithelial cell lines of either prostate (PrEC and RWPE) or breast (H16N2 and HME) origin. To explore miRNAs regulated by PRC2 globally, we knocked-down EZH2 in DU145 prostate cancer cells with a validated siRNA targeting EZH2 and monitored miRNA expression with Illumina BeadChips. In this study, we sought to explore the regulatory axis between PRCs and whether miRNAs mediate the synergy between the two complexes. The mechanism of how PRC2 and PRC1 coordinate their functions is still unclear. Like PRC2 component EZH2, BMI1 and RING2 have been shown to be elevated in a number of tumor types ( Glinsky et al., 2005 Sanchez-Beato et al., 2006) and regulate self-renewal of embryonic stem cells and cancer stem cells ( Galmozzi et al., 2006 Valk-Lingbeek et al., 2004). ![]() The prevailing hypothesis is that PRC2 mediated trimethylation of H3K27 recruits PRC1 to gene loci, which enacts chromatin condensation and epigenetic silencing of target genes ( Bracken and Helin, 2009). Accumulating evidence suggests that increased activity of PRC2 is oncogenic as measured by cell proliferation ( Bracken et al., 2003 Varambally et al., 2002), cell invasion ( Cao et al., 2008 Kleer et al., 2003), anchorage-independent growth ( Bracken et al., 2003 Kleer et al., 2003), maintenance of tumor-initiating cells, tumor xenograft growth ( Yu et al., 2007b) and metastasis in vivo ( Min et al.).Ī key collaborator of PRC2 in epigenetic silencing is human PRC1, which is comprised of B lymphoma Mo-MLV insertion region 1 (BMI1), RING1 (also known as RING1A or RNF1) and RING2 (also known as RING1B or RNF2), and functions as a multi-protein complex to ubiquitinate histone H2A at lysine 119 (uH2A) ( Cao et al., 2005 Wang et al., 2004). ![]() Also, miR-26a was reported to target EZH2 in cancer and myogenesis (Lu et al. ![]() Friedman et al., 2009 Varambally et al., 2008 Wang et al.). Loss of microRNA (miRNA)-101, has been shown to be one mechanism that leads to elevated EZH2 and PRC2 activity in tumors ( Cao et al. EZH2, which is the enzymatic component of PRC2, is elevated in aggressive forms of prostate and breast cancer ( Kleer et al., 2003 Varambally et al., 2002), as well as multiple other solid tumors ( Matsukawa et al., 2006 Sudo et al., 2005). PRC2 is thought to be recruited to target genomic loci by long non-coding RNAs (ncRNAs) such as HOTAIR ( Gupta et al., 2010 Kaneko et al. Key components of the human PRC2 include the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), and its binding partners, Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 (SUZ12), which function as a multi-subunit complex that trimethylates histone H3K27. Dysregulation of PcG proteins can contribute to a number of human diseases, most notably, cancer ( Bracken and Helin, 2009 Margueron and Reinberg, 2011). Both PRC1 and PRC2 play a critical role in the maintenance of normal and cancer stem cell populations ( Ezhkova et al., 2009 Lukacs et al., 2010 Pietersen et al., 2008). PcG proteins form multiprotein repressive complexes called PRCs. Polycomb group (PcG) proteins are evolutionarily conserved regulators of gene silencing important in metazoan development ( Surface et al.), stem cell pluripotency ( Pereira et al.), and X chromosome inactivation ( Cao et al., 2002 Margueron and Reinberg, 2011). ![]()
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