BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer.
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.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Yuhki
Y
Yokoyama
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Hengrui
H
Zhu
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Jeong Heon
JH
Lee
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
Andrew V
AV
Kossenkov
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sherry Y
SY
Wu
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
Jayamanna M
JM
Wickramasinghe
Molecular and Cellular Oncology Program, The Wistar Institute, Philadelphia, Pennsylvania.
Xiangfan
X
Yin
Institute for Regenerative Medicine, Epigenetics Program, and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania.
Katherine C
KC
Palozola
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Alessandro
A
Gardini
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.|Molecular and Cellular Oncology Program, The Wistar Institute, Philadelphia, Pennsylvania.
Louise C
LC
Showe
Institute for Regenerative Medicine, Epigenetics Program, and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania.
Kenneth S
KS
Zaret
Molecular and Cellular Oncology Program, The Wistar Institute, Philadelphia, Pennsylvania.
Qin
Q
Liu
Molecular and Cellular Oncology Program, The Wistar Institute, Philadelphia, Pennsylvania.
David
D
Speicher
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Jose R
JR
Conejo-Garcia
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
James E
JE
Bradner
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.|Mayo Clinic, Rochester, Minnesota.
Zhiguo
Z
Zhang
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Anil K
AK
Sood
Mayo Clinic, Rochester, Minnesota.
Tamas
T
Ordog
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
Benjamin G
BG
Bitler
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania. rzhang@wistar.org bbitler@wistar.org.
Rugang
R
Zhang
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D050697:Retinal Dehydrogenase; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D001381:Azepines; D018797:Cell Cycle Proteins; D002945:Cisplatin; D009687:Nuclear Proteins; D050697:Retinal Dehydrogenase; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C510223:ALDH1A1 protein, human