Abstract
CHD1 is required for the growth of PTEN-deficient prostate cancer cells in vitro and in vivo.
Major finding: CHD1 is required for the growth of PTEN-deficient prostate cancer cells in vitro and in vivo.
Mechanism: PTEN induces GSK3β-mediated phosphorylation of CHD1 in the degron domain, promoting CHD1 degradation.
Impact: Synthetic-essential genes may reveal druggable targets in tumors with tumor-suppressor deficiencies.
In cancers with tumor suppressor gene deletions, targeting synthetic-lethal vulnerabilities has emerged as a treatment strategy and has been validated by the success of PARP inhibitors in BRCA-deficient tumors. Zhao and colleagues sought to identify synthetic-lethal interactions in prostate cancer by screening for “synthetic-essential” genes that were occasionally deleted in cancer but retained when the tumor suppressor PTEN was deleted and thus might represent therapeutic targets. Analysis of data from The Cancer Genome Atlas found that, although the gene encoding the chromatin remodeling protein CHD1 was deleted in 7% to 10% of prostate cancers, its deletion was mutually exclusive to PTEN-deficiency, suggesting that CHD1 might be required for tumor progression in PTEN-deficient prostate cancer. Indeed, in PTEN-deficient prostate cancer cells, CHD1 depletion inhibited colony formation and induced cell death, and, in vivo, CHD1 depletion reduced the growth of PTEN-deficient xenografts. Moreover, CHD1 depletion had little effect on PTEN-proficient prostate cancer cell growth in vitro and in vivo, supporting the synthetic-essential relationship between PTEN and CHD1. Re-expression of PTEN in deficient cells results in a reduction in CHD1 protein levels. Mechanistically, PTEN destabilized CHD1 by inducing GSK3β-mediated phosphorylation of the CHD1 degron, resulting in proteasomal degradation of CHD1. Conversely, PTEN deficiency stabilized CHD1, allowing CHD1 to recognize and bind to trimethylated histone 3 lysine 4, a mark of transcriptional activation, and promote transcription of NF-κB target genes. In addition to identifying a synthetic-essential relationship between PTEN and CHD1, with CHD1 required for survival in PTEN-deficient prostate cancer cells, these findings indicate that CHD1 may be a potential therapeutic target in patients with PTEN-deficient cancer. Further, the identification of synthetic-essential genes may uncover targetable vulnerabilities for other tumor suppressor deficiencies and in other tumor types.
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