Inhibition of BET protein BRD4 activity synergizes with cisplatin in ovarian cancer by targeting ALDH activity through an ALDH1A1 super-enhancer and the associated enhancer RNA

The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity contributes to chemotherapy resistance. Here we report that inhibition of the BET protein BRD4 potentiates the tumor suppressive effects of cisplatin by targeting ALDH activity. The clinically applicable small molecule BET inhibitor JQ1 synergized with cisplatin by suppressing the growth of epithelial ovarian cancer cells both in vitro and in vivo. This correlated with the suppression of ALDH activity and ALDH1A1 gene expression. BRD4 regulates ALDH1A1 gene transcription through a super-enhancer and expression of its associated enhancer RNA. Thus, targeting the BET protein BRD4 using clinical applicable small molecule inhibitors such as JQ1 is a promising strategy to enhance cisplatin response. Overall design: DMSO and JQ1 treated cells were assayed by BRD4 CHIP-seq and RNA-seq