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Overexpression of the androgen receptor (AR) is the primary cause of development of castration-resistant prostate cancer (CRPC), although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq analysis revealed AR as the top pathway altered after SMAD3 knockdown in prostate cancer cells. SMAD3 knockdown decreased levels of AR, AR-V7 and AR target gene transcripts, 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 or SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR in terms of AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. This study suggests that SMAD3 could be targeted to downregulate AR expression and activity and as potential anti-prostate cancer therapy. Citation Format: Hee-Young Jeon, Majid Pornour, Hyunju Ryu, Sudeep Khadka, Rui Xu, Jihyun Jang, Deqiang Li, Hegang Chen, Arif Hussain, Ladan Fazli, Martin Gleave, Xuesen Dong, Qianben Wang, Christopher Barbieri, Jianfei Qi. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1454. |
