SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Issue 6 (2nd February 2023)

• Record Type: Journal Article
• Authors: Jeon, Hee-Young; Pornour, Majid; Ryu, Hyunju; Khadka, Sudeep; Xu, Rui; Jang, Jihyun; Li, Deqiang; Chen, Hegang; Hussain, Arif; Fazli, Ladan; Gleave, Martin; Dong, Xuesen; Huang, Furong; Wang, Qianben; Barbieri, Christopher; Qi, Jianfei
• Is Part Of: Nucleic acids research. Volume 51:Issue 6(2023)
• Page Start: 2655
• Page End: 2670
• Publication Date: 2023-02-02
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkad043
• Languages: English
• ISSNs: 0305-1048

Abstract

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.