BET inhibitors suppress ALDH activity by targeting ALDH1A1 super-enhancer in ovarian cancer

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

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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 stemrelated 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 smallmolecule 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.

Original languageEnglish (US)
Pages (from-to)6320-6330
Number of pages11
JournalCancer Research
Volume76
Issue number21
DOIs
StatePublished - Nov 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yokoyama, Y., Zhu, H., Lee, J. H., Kossenkov, A. V., Wu, S. Y., Wickramasinghe, J. M., Yin, X., Palozola, K. C., Gardini, A., Showe, L. C., Zaret, K. S., Liu, Q., Speicher, D., Conejo-Garcia, J. R., Bradner, J. E., Zhang, Z., Sood, A. K., Ordog, T., Bitler, B. G., & Zhang, R. (2016). BET inhibitors suppress ALDH activity by targeting ALDH1A1 super-enhancer in ovarian cancer. Cancer Research, 76(21), 6320-6330. https://doi.org/10.1158/0008-5472.CAN-16-0854