2. Academic Validation
  3. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer

SMAD3 promotes expression and activity of the androgen receptor in prostate cancer

  • Nucleic Acids Res. 2023 Feb 2;gkad043. doi: 10.1093/nar/gkad043.
Hee-Young Jeon 1 2,  Majid Pornour 1 2,  Hyunju Ryu 1 2,  Sudeep Khadka 1 2,  Rui Xu 1 3,  Jihyun Jang 4,  Deqiang Li 4,  Hegang Chen 5,  Arif Hussain 1 2 6,  Ladan Fazli 7,  Martin Gleave 7,  Xuesen Dong 7,  Furong Huang 8,  Qianben Wang 8,  Christopher Barbieri 9,  Jianfei Qi 1 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA.
  • 2 Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
  • 3 Institute of Marine and Environmental Technology, University of Maryland, Baltimore, MD, USA.
  • 4 Department of Cardiac Surgery, University of Maryland, Baltimore, MD, USA.
  • 5 Department of Epidemiology and Public Health, University of Maryland, Baltimore, MD, USA.
  • 6 Baltimore VA Medical Center, Baltimore, MD, USA.
  • 7 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
  • 8 Department of Pathology and Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA.
  • 9 Department of Urology, Weill Cornell Medical College, NY, NY, USA.
PMID: 36727462 DOI: 10.1093/nar/gkad043
Abstract

Overexpression of Androgen Receptor (AR) is the primary cause of castration-resistant prostate Cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ∼50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate Cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate Cancer and CRPC compared with primary prostate Cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate Cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate Cancer.

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