Bromodomain-containing protein 4 activates androgen receptor transcription and promotes ovarian fibrosis in PCOS
Daojuan Wang,
Zhengquan Zhu,
Yu Fu,
Qiong Zhang,
Yi Zhang,
Tingyu Wang,
Yajing Weng,
Yanting Wen,
Wangsen Cao,
Gaojian Tao,
Yong Wang
Affiliations
Daojuan Wang
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Department of Pain Management, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Zhengquan Zhu
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
Yu Fu
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
Qiong Zhang
Department of Obstetrics and Gynecology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
Yi Zhang
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
Tingyu Wang
Department of Pain Management, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Yajing Weng
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
Yanting Wen
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
Wangsen Cao
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Department of Nephrology, Yangzhou Precision Research Institute of Kidney Disease, Northern Jiangsu People’s Hospital, Teaching Hospital of Nanjing University Medical School, Yangzhou 225009, China; Corresponding author
Gaojian Tao
Department of Pain Management, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; Corresponding author
Yong Wang
The Affiliated Nanjing Drum Tower Hospital, and State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China; Corresponding author
Summary: Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation “reader” BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.
