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 2

BRG1 is required in PTEN-deficient PCa cells.

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BRG1 is required in PTEN-deficient PCa cells. (A) MTT analysis of PCa ce...
(A) MTT analysis of PCa cells with or without BRG1 KD (shBRG1). (B) Transwell (upper right) and soft agar (lower right) images of BRG1-KD PC3 cells with or without WT or mutant BRG1 (K798R) restoration. Scale bar: 1 mm. (C) IB of lysates and cell growth measurements in control and BRG1-KD 22RV-1 and LAPC4 cells with or without PTEN KD (shPTEN). (D) Measurement of subcutaneous tumor growth of control and PTEN-KD 22RV-1 cells with or without BRG1 depletion (shBRG1) (n = 6, 2-way ANOVA followed by Tukey’s multiple comparisons test); a representative image is shown. Scale bar: 1 cm. (E) Representative BLI images for control and BRG1-KD PC3 cells at day 0 (upper panels) and day 60 (lower panels). Limb metastasis is calculated as the mean ± SEM of the bioluminescence signal at day 60 (n = 6 per group, 2-tailed Student’s t test). (F) Representative x-ray images of bone metastasis are shown on the left, and the osteolytic area is quantified on the right (n = 8, 2-tailed Student’s t test). (G) TRAP- and E-cadherin–stained images as indicated. T, tumor cell; M, bone marrow; arrow, TRAP-positive cell. Scale bar: 50 μm. Data represent mean ± SEM of 3 independent experiments. Statistical analyses were performed by 2-way ANOVA followed by Tukey’s multiple comparisons test (A and C). **P < 0.01.