Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer.

Abstract

Loss of phosphatase and tensin homolog (PTEN) represents one hallmark of prostate cancer (PCa). However, restoration of PTEN or inhibition of the activated PI3K/AKT pathway has shown limited success, prompting us to identify obligate targets for disease intervention. We hypothesized that PTEN loss might expose cells to unique epigenetic vulnerabilities. Here, we identified a synthetic lethal relationship between PTEN and Brahma-related gene 1 (BRG1), an ATPase subunit of the SWI/SNF chromatin remodeling complex. Higher BRG1 expression in tumors with low PTEN expression was associated with a worse clinical outcome. Genetically engineered mice (GEMs) and organoid assays confirmed that ablation of PTEN sensitized the cells to BRG1 depletion. Mechanistically, PTEN loss stabilized BRG1 protein through the inhibition of the AKT/GSK3β/FBXW7 axis. Increased BRG1 expression in PTEN-deficient PCa cells led to chromatin remodeling into configurations that drove a protumorigenic transcriptome, causing cells to become further addicted to BRG1. Furthermore, we showed in preclinical models that BRG1 antagonist selectively inhibited the progression of PTEN-deficient prostate tumors. Together, our results highlight the synthetic lethal relationship between PTEN and BRG1 and support targeting BRG1 as an effective approach to the treatment of PTEN-deficient PCa.

• Authors: Yufeng Ding, Ni Li, Baijun Dong, Wangxin Guo, Hui Wei, Qilong Chen, Huairui Yuan, Ying Han, Hanwen Chang, Shan Kan, Xuege Wang, Qiang Pan, Ping Wu, Chao Peng, Tong Qiu, Qintong Li, Dong Gao, Wei Xue, Jun Qin
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 2 Pg. 759-773 (02 01 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 30496141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromosomal Proteins, Non-Histone
• Nuclear Proteins
• SWI-SNF-B chromatin-remodeling complex
• Transcription Factors
• PTEN Phosphohydrolase
• PTEN protein, human
• SMARCA4 protein, human
• DNA Helicases

Topics

• Animals
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• DNA Helicases (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Nude
• Mice, Transgenic
• Neoplasms, Experimental (genetics, metabolism, mortality, pathology)
• Nuclear Proteins (genetics, metabolism)
• PC-3 Cells
• PTEN Phosphohydrolase (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, mortality, pathology)
• Signal Transduction (genetics)
• Transcription Factors (genetics, metabolism)