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Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer
Yufeng Ding, … , Wei Xue, Jun Qin
Yufeng Ding, … , Wei Xue, Jun Qin
Published November 29, 2018
Citation Information: J Clin Invest. 2019;129(2):759-773. https://doi.org/10.1172/JCI123557.
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Research Article Cell biology Oncology

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

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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

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Figure 4

PTEN/AKT/GSK3β modulates BRG1 stability in PCa cells.

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PTEN/AKT/GSK3β modulates BRG1 stability in PCa cells.
(A) IB analysis of...
(A) IB analysis of the indicated proteins in mouse AP lysates (mAP) and human prostate cell lines as indicated. (B) Representative BRG1 staining in prostate sections of WT and PtenPC–/– mice. Scale bar: 50 μm. (C) IB as indicated (left) and BRG1 mRNA levels (right) in control and PTEN-overexpressing PC3 cells. (D) Detection of BRG1 ubiquitination by IP and IB as indicated. (E) Examination of BRG1 protein and mRNA in PC3 cells transfected with scramble or AKT oligonucleotides. (F) IB analysis of PC3 cells treated with DMSO or 20 μM LY294002 with or without MG132. (G) IB analysis of whole cell lysates (WCL) and IP from PC3 cells as indicated. (H) IB analysis of PC3 cells transfected with scramble or AKT oligonucleotides with or without GSK3β KD at the indicated times. (I) Representative images of BRG1 and PTEN staining. The box plot shows the relative BRG1 level in PTEN-low and PTEN-high patients (an Asian radical prostatectomy cohort). Kendall’s tau-beta was used to test for correlations in the IHC results. Scale bar: 250 μm. Quantitative data from experiments performed in triplicate, 2-tailed Student’s t test (C and E).
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