BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer
Year: 2016
Type: article
Abstract: The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. The clinically applicable small-molecule BET inhibitor JQ1 suppressed the outgrowth of cisplatin-treated ovarian cancer cells both in vitro and in vivo Combination of JQ1 and cisplatin improved the survival of ovarian cancer-bearing mice in an orthotopic model. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and other stem-related genes in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using clinically applicable small-molecule inhibitors, such as JQ1, is a promising strategy for targeting ALDH activity in epithelial ovarian cancer. Cancer Res; 76(21); 6320-30. ©2016 AACR.
Source: Cancer Research
Authors: Yuhki Yokoyama, Hengrui Zhu, Jeong Heon Lee, Andrew V. Kossenkov, Sherry Y. Wu, Jayamanna M. Wickramasinghe, Xiangfan Yin, Katherine C. Palozola, Alessandro Gardini, Louise C. Showe, Kenneth S. Zaret, Qin Liu, David Speicher, Jose R. Conejo-Garcia, James E. Bradner, Zhiguo Zhang, Anil K. Sood, Tamas Ordog, Benjamin G. Bitler, Rugang Zhang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1093965436, G1403651065, G1634253349, Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer, G281858550, G3362314685, G3402416433, G3925678120, G393472261, Predoctoral Training Program in Genetics, Integration of Biomarker Signatures from Peripheral Blood for Diagnosis, Prognosis, Remission and Recurrence of Lung Cancer, The University of Texas M. D. Anderson Cancer Center SPORE in Ovarian Cancer, Mayo Clinic Comprehensive Cancer Center Support Grant, Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer, Consolidated Basic Cancer Research Program
OpenAlex ID: W2547320292