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 3

Brg1 loss inhibits Pten loss–induced tumorigenesis in mice.

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Brg1 loss inhibits Pten loss–induced tumorigenesis in mice. (A) IHC stai...
(A) IHC staining of BRG1 in prostate sections of 5-month-old PtenPC–/–, and PtenPC–/–; Brg1PC–/– mice. Scale bar: 50 μm. (B) Representative BLI images of PtenPC–/–, and Pten PC–/–; Brg1PC–/– mice at 5 months of age. Quantification of BLI is shown on the right (n = 5, 2-tailed Student’s t test). (C) H&E-stained sections of representative anterior prostate (AP), dorsal-lateral prostate (DLP), and ventral prostate (VP). Scale bars: 100 μm. Original magnification for the inset, × 50. (D) Quantification of histology grade in PtenPC–/– (n = 10), and PtenPC–/–; Brg1PC–/– mice (n = 6) at 5 months of age (χ2 test). (E) H&E, AR, and SMAα staining of the DLP in PtenPC–/– (with the appearance of invasive adenocarcinoma) and PtenPC–/–; Brg1PC–/– mice. Scale bars: 100 μm. (F) Representative images of organoids from Pten-WT and Pten-null prostates with or without BRG1 KD (shBRG1). Quantitation of organoid size is representative of 3 experiments shown on the right (2-tailed Student’s t test). Scale bar: 200 μm. (G) Immunostaining of Ki67, AR, and P63 as indicated. Scale bar: 50 μm. (H) Organoid images derived from prostatic Myc-overexpressing mice (Hi-Myc) with or without BRG1 KD (shBRG1); quantitative results are representative of 3 experiments shown at the bottom (2-tailed Student’s t test). Scale bar: 400 μm. **P < 0.01.