Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions1,2,3. 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.
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Gene Expression Omnibus
We thank S. W. Hayward for the BPH1 cell line; P. Shepherd for the PDX models, Y. Chen for Flag-tagged β-TrCP plasmid; T. Gutschner for CRISPR X330-Cherry vector; Y. L. Deribe for the HA-tagged PTEN plasmid; S. Jiang and K. Zhao for assistance in maintenance of mouse colonies; Q. E. Chang for assistance in IHC slides scanning; and the MD Anderson Sequencing and Microarray Facility (SMF) and Flow Cytometry and Cellular Imaging Core Facility. This work was supported in part by the Odyssey Program and Theodore N. Law Endowment For Scientific Achievement at The University of Texas MDACC 600649-80-116647-21 (D.Z.); DOD Prostate Cancer Research Program (PCRP) Idea Development Award–New Investigator Option W81XWH-14-1-0576 (X. Lu); NIH Pathway to Independence (PI) Award (K99/R00)-NCI: 1K99CA194289 (G.W.); DOD PCRP W81XWH-14-1-0429 (P.Dey.); CPRIT research training award RP140106-DC (D.C.); NIH grants P01 CA117969 (R.A.D.) and R01 CA084628 (R.A.D.).
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β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer
Cell Death & Differentiation (2018)