SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. Academic Article uri icon

Overview

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.

publication date

  • April 11, 2023

Research

keywords

  • Prostatic Neoplasms
  • Prostatic Neoplasms, Castration-Resistant
  • Smad3 Protein

Identity

PubMed Central ID

  • PMC10085708

Scopus Document Identifier

  • 85152166635

Digital Object Identifier (DOI)

  • 10.1093/nar/gkad043

PubMed ID

  • 36727462

Additional Document Info

volume

  • 51

issue

  • 6