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

Publication ,  Journal Article
Jeon, H-Y; Pornour, M; Ryu, H; Khadka, S; Xu, R; Jang, J; Li, D; Chen, H; Hussain, A; Fazli, L; Gleave, M; Dong, X; Huang, F; Wang, Q ...
Published in: Nucleic Acids Res
April 11, 2023

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.

Duke Scholars

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

April 11, 2023

Volume

51

Issue

6

Start / End Page

2655 / 2670

Location

England

Related Subject Headings

  • Smad3 Protein
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • Prostate
  • Male
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Developmental Biology
  • Cell Line, Tumor
 

Citation

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Jeon, H.-Y., Pornour, M., Ryu, H., Khadka, S., Xu, R., Jang, J., … Qi, J. (2023). SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Nucleic Acids Res, 51(6), 2655–2670. https://doi.org/10.1093/nar/gkad043
Jeon, Hee-Young, Majid Pornour, Hyunju Ryu, Sudeep Khadka, Rui Xu, Jihyun Jang, Deqiang Li, et al. “SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.Nucleic Acids Res 51, no. 6 (April 11, 2023): 2655–70. https://doi.org/10.1093/nar/gkad043.
Jeon H-Y, Pornour M, Ryu H, Khadka S, Xu R, Jang J, et al. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Nucleic Acids Res. 2023 Apr 11;51(6):2655–70.
Jeon, Hee-Young, et al. “SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.Nucleic Acids Res, vol. 51, no. 6, Apr. 2023, pp. 2655–70. Pubmed, doi:10.1093/nar/gkad043.
Jeon H-Y, Pornour M, Ryu H, Khadka S, Xu R, Jang J, Li D, Chen H, Hussain A, Fazli L, Gleave M, Dong X, Huang F, Wang Q, Barbieri C, Qi J. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Nucleic Acids Res. 2023 Apr 11;51(6):2655–2670.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

April 11, 2023

Volume

51

Issue

6

Start / End Page

2655 / 2670

Location

England

Related Subject Headings

  • Smad3 Protein
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • Prostate
  • Male
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Developmental Biology
  • Cell Line, Tumor