Data from BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer

Abstract

<div>Abstract<p>People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (<i>EZH2</i>), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of <i>BRD4</i> decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis <i>in vitro</i> and suppressed tumor growth <i>in vivo</i>. We further found that suppression of <i>BRD4</i> decreased the mRNA and protein levels of <i>EZH2</i>, which was reversed by ectopic expression of <i>C-MYC</i>. In particular, individual silencing of <i>BRD4</i> using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to <i>EZH2</i> promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates <i>EZH2</i> transcription through upregulation of <i>C-MYC</i>, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease. <i>Mol Cancer Ther; 15(5); 1029–42. ©2016 AACR</i>.</p></div>