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 February 1, 2019; First 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 1

Identification of the epigenetic regulator required for PTEN-deficient PCa cells.

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Identification of the epigenetic regulator required for PTEN-deficient P...
(A) A schematic of the screening workflow for the chromatin regulator based on CRISPR-Cas9 screening in PTEN-WT and PTEN-KD (shPTEN) 22RV-1 cells. (B) Scatter plot showing the normalized counts for each sgRNA in the original pool (day 0) relative to the samples taken after 45 days of cultures (MaGeCK and MAGeCK-VISPR analysis). (C) Venn diagram showing the number of overlapping genes between the cells as indicated. (D) siRNA KD of 32 candidate genes and their effects on the growth of PTEN-WT and PTEN-KD 22RV-1 cells. Quantitative results shown are representative of 4 experiments. Genes highlighted in red box exhibited the differential growth effects between PTEN-WT and PTEN-KD 22RV-1 cells. (E) BRG1 staining indexes using a 10-point quantification scale in cohorts of normal prostate tissue (n = 87) and prostate tumors (n = 122) (Wilcoxon’s rank sum test). Scale bar: 50 μm. (F) Kaplan-Meier plot of recurrence after radical prostatectomy based on the BRG1 expression index in patients (P values by log-rank test). Scale bar: 200 μm. (G) Kaplan-Meier plots based on BRG1 expression in PTEN-low and PTEN-high tumors (log-rank test).