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

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 8

Targeting the SWI/SNF remodeling complex inhibits the progression of PTEN-deficient PCa.

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Targeting the SWI/SNF remodeling complex inhibits the progression of PTE...
(A) Relative growth of PTEN-WT and PTEN-KD 22RV-1 cells treated with PFI-3 at different concentrations, as indicated. (B) Effects of PFI-3 treatment (50 mg/kg, once per week) on xenografts, as indicated (n = 6 per group, 2-way ANOVA followed by Tukey’s multiple comparisons test). Treatment started when tumors reached 50–100 mm3. (C and D) Representative images of PTEN-deficient (C) or Myc-overexpressing (D) organoids treated with vehicle or PFI-3 (100 nM; 7 days). Scale bar: 200 μm. (E) MRI analysis of prostates in PtenPC–/– mice treated with PFI-3 for 45 days (50 mg/kg, starting at 2.5 months of age; T0). Prostate tumors are indicated by red dotted circles, and relative tumor volume is shown at the bottom (n = 5, 2-tailed Student’s t test). Red asterisks indicate bladders. (F) H&E staining of prostates from vehicle- and PFI-3-treated PtenPC–/– mice. Histology quantitation is indicated at the bottom (n = 5, χ2 test). Scale bar: 100 μm. (G) PTEN loss stabilized BRG1 through the inhibition of the AKT/GSK3β/FBXW7-mediated proteasome pathway. Consequently, BRG1 remodeled the chromatin configuration and initiated a PTEN-dependent BRG1 transcriptome to sustain tumor cell growth. Thus, targeting BRG1 represents a promising approach against PTEN-mutated prostate tumors. n = 3 independent experiments, 2-tailed Student’s t test (A, C, and D). *P < 0.05; **P < 0.01.