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BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer.

Publication ,  Journal Article
Yokoyama, Y; Zhu, H; Lee, JH; Kossenkov, AV; Wu, SY; Wickramasinghe, JM; Yin, X; Palozola, KC; Gardini, A; Showe, LC; Zaret, KS; Liu, Q ...
Published in: Cancer Res
November 1, 2016

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 1, 2016

Volume

76

Issue

21

Start / End Page

6320 / 6330

Location

United States

Related Subject Headings

  • Triazoles
  • Transcription Factors
  • Retinal Dehydrogenase
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Neoplasms, Glandular and Epithelial
  • Mice
  • Humans
  • Female
 

Citation

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Yokoyama, Y., Zhu, H., Lee, J. H., Kossenkov, A. V., Wu, S. Y., Wickramasinghe, J. M., … Zhang, R. (2016). BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res, 76(21), 6320–6330. https://doi.org/10.1158/0008-5472.CAN-16-0854
Yokoyama, Yuhki, Hengrui Zhu, Jeong Heon Lee, Andrew V. Kossenkov, Sherry Y. Wu, Jayamanna M. Wickramasinghe, Xiangfan Yin, et al. “BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer.Cancer Res 76, no. 21 (November 1, 2016): 6320–30. https://doi.org/10.1158/0008-5472.CAN-16-0854.
Yokoyama Y, Zhu H, Lee JH, Kossenkov AV, Wu SY, Wickramasinghe JM, et al. BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res. 2016 Nov 1;76(21):6320–30.
Yokoyama, Yuhki, et al. “BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer.Cancer Res, vol. 76, no. 21, Nov. 2016, pp. 6320–30. Pubmed, doi:10.1158/0008-5472.CAN-16-0854.
Yokoyama Y, Zhu H, Lee JH, Kossenkov AV, Wu SY, Wickramasinghe JM, Yin X, Palozola KC, Gardini A, Showe LC, Zaret KS, Liu Q, Speicher D, Conejo-Garcia JR, Bradner JE, Zhang Z, Sood AK, Ordog T, Bitler BG, Zhang R. BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res. 2016 Nov 1;76(21):6320–6330.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 1, 2016

Volume

76

Issue

21

Start / End Page

6320 / 6330

Location

United States

Related Subject Headings

  • Triazoles
  • Transcription Factors
  • Retinal Dehydrogenase
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Neoplasms, Glandular and Epithelial
  • Mice
  • Humans
  • Female