Regulation of Polycomb Repressive Complex 1 by EZH2 Regulated microRNAs in Cancer

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second most common cause of cancer-related death in men in the United States. While multiple molecular events contribute to prostate cancer progression, it has become increasingly evident that epigenetic changes play pivotal roles in regulating cancer development. Polycomb repressive complex (PRC) members maintain the gene expression status of a cell by epigenetically modifying histone proteins. Histone methyltransferase EZH2, an oncogenic PRC2 member, initiates the transcriptional repression by trimethylating histone H3 at lysine 27. We have shown that EZH2 is overexpressed in aggressive prostate and breast cancers, predicts disease outcome, and is required for cancer cell survival. In addition, our studies have shown that EZH2 down-regulates multiple tumor suppressors and a genomic loss of microRNA-101 results in unregulated expression of EZH2 in aggressive tumors. While the role of EZH2 in regulating protein-coding genes is known, its role in regulating microRNA (miR) expression has not been studied. MiRs are critical regulators of cellular functions and are commonly altered in cancers including down regulation of several tumor suppressor miRs. Thus, we hypothesize that transcriptional repressor EZH2 plays a key role in regulating microRNA expression by epigenetic silencing and EZH2-regulated miRs play critical roles in PCa progression. Our preliminary data suggest that EZH2 down regulates multiple miRs, including miR-203 and the miR-200a, miR-200bc family. MiR-203 and mir-200a, bc in turn regulate PRC1 members, BMI1 and RING2. Thus the aims of this proposal are to extend these findings and gain further insights into the regulation of miRs by EZH2 and the role of these miRs in PCa development. In order to accomplish these goals, in Specific Aim 1, we will investigate the role of EZH2 in regulating miR expression in multiple cell types. We will first perform miR profiling using RNA from prostate cell lines in which EZH2 expression is modulated. We will validate the EZH2 regulated miR expression in prostate tumor tissues and correlate them with EZH2 expression. In Specific Aim 2, we will investigate the role of EZH2-regulated miRs in PCa and their role in targeting the PRC1 members. In Specific Aim 3, we will investigate the role of EZH2-regulated miRs in prostate tumorigenesis. We will use select EZH2-regulated miRs that are directly repressed by EZH2 and characterize the consequences of their modulation using both cell line and in vivo models of PCa. Relevance to Public Health: Successful completion of the proposed work will provide evidence for an intricate network of miR and epigenetic regulators in PCa development and identify potential diagnostic and prognostic markers, which in turn may improve PCa therapy through better diagnosis and disease monitoring. Our results may ultimately provide credence for therapeutic re-introduction of EZH2-repressed tumor suppressor miRs in cancer.