Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer

• Published in: Nature (London) Vol. 542; no. 7642; pp. 484 - 488
• Main Authors: Zhao, Di, Lu, Xin, Wang, Guocan, Lan, Zhengdao, Liao, Wenting, Li, Jun, Liang, Xin, Chen, Jasper Robin, Shah, Sagar, Shang, Xiaoying, Tang, Ming, Deng, Pingna, Dey, Prasenjit, Chakravarti, Deepavali, Chen, Peiwen, Spring, Denise J., Navone, Nora M., Troncoso, Patricia, Zhang, Jianhua, Wang, Y. Alan, DePinho, Ronald A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.02.2017; Nature Publishing Group
• Subjects: 631/67/589/466; 631/67/69; beta-Transducin Repeat-Containing Proteins - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer genetics; Cancer research; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly - genetics; DNA Helicases - chemistry; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Expression Regulation, Neoplastic; Genes; Genes, Essential - genetics; Genomes; Glycogen Synthase Kinase 3 beta - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Kinases; letter; Lysine - metabolism; Male; Methylation; Molecular Targeted Therapy; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NF-kappa B - metabolism; Phosphorylation; Physiological aspects; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteasome Endopeptidase Complex - metabolism; Protein Stability; Proteolysis; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Science; Tumor Necrosis Factor-alpha - metabolism; Tumors; Ubiquitination
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature21357

The gene CHD1 is synthetic essential in PTEN-deficient prostate and breast cancers. CHD1 is required in PTEN-deficient tumours Here the authors search in prostate cancer cohorts for genes that are always retained when the tumour-suppressor gene PTEN is deleted. Such genes confer 'synthetic essentiality', which means they are specifically required in PTEN-deficient tumours. The authors identify the chromatin remodelling factor CHD1 and show that it is regulated by PTEN. Deletion of CHD1 causes reduced tumour growth, underlining the potential of this approach for the discovery of novel therapeutic targets. Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions 1 , 2 , 3 . Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify ‘synthetic-essential’ genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the β-TrCP-mediated ubiquitination–proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF–NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of ‘trackable’ targets in cancers that harbour specific tumour-suppressor deficiencies.