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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 5

The PTEN/AKT/GSK3β axis modulates BRG1 stability through the FBXW7-dependent ubiquitin proteasome pathway.

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The PTEN/AKT/GSK3β axis modulates BRG1 stability through the FBXW7-depen...
(A) Sequence alignment of the putative GSK3β phosphorylation sites at S1417 and S1421 of BRG1. (B) In vitro kinase assays depicting major GSK3β phosphorylation sites in BRG1. (C) IB analysis of WCL and immunoprecipitates from control and PTEN-overexpressing PC3 cells treated with CHIR-99021 or λ-phosphatase as indicated. (D) Lysates from control and FBXW7-overexpressing cells were subjected to IP with an anti-BRG1 antibody, and ubiquitinated BRG1 was detected by an anti-Ub antibody. (E) IB analysis of PC3 cells transfected with scramble or AKT oligonucleotides with or without FBXW7 KD (shFBXW7). (F) Flag-tagged WT, BRG1-SA, and BRG1-SD proteins were incubated with SCF-FBXW7 complex as indicated and then subjected to Western blotting. (G) IB analysis of the indicated protein in WCL and immunoprecipitates from 293T cells transfected with HA-tagged FBXW7 and Flag-tagged BRG1, BRG-SA, or BRG1-SD. (H) IB analysis of the indicated protein in WT, SA, and SD cells. (I) WT, SA, and SD cell lysates were subjected to IP with the indicated antibodies. (J) Volume of subcutaneous tumors derived from WT, SA, and SD cells (n = 6, 2-way ANOVA followed by Tukey’s multiple comparisons test). Scale bar: 1 cm. (K) Representative image of BRG1, P-1417/1421, and PTEN expression in lysates from PCa samples (upper panel). Pearson’s correlations among BRG1, P-1417/1421, and PTEN in PCa specimens are summarized in the heatmap (n = 30). **P < 0.01.
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