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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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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Author notes

    • Xin Lu
    •  & Guocan Wang

    These authors contributed equally to this work.


  1. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Di Zhao
    • , Xin Lu
    • , Guocan Wang
    • , Zhengdao Lan
    • , Wenting Liao
    • , Xin Liang
    • , Jasper Robin Chen
    • , Sagar Shah
    • , Xiaoying Shang
    • , Pingna Deng
    • , Prasenjit Dey
    • , Deepavali Chakravarti
    • , Peiwen Chen
    • , Denise J. Spring
    • , Y. Alan Wang
    •  & Ronald A. DePinho
  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jun Li
    • , Ming Tang
    •  & Jianhua Zhang
  3. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

  4. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Nora M. Navone
  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Patricia Troncoso


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D.Z., Y.A.W. and R.A.D. conceived the original hypothesis of synthetic essentiality. D.Z. designed and performed cell-line-derived xenograft-model and signalling-pathway experiments. X.Lu and X.S. performed the patient-derived xenograft-model experiments and siRNA treatment. G.W. performed microarray and GSEA analyses. Z.L. performed ChIP–seq experiments, and M.T. performed ChIP–seq data analysis. W.L. reviewed and scored human tissue sections. P.T. and W.L. provided the human prostate cancer tissue sections. J.L., J.Z. and J.R.C. performed TCGA data analyses. X.Li., S.S., J.R.C., P.Den. and P.C. provided technical support. N.M.N. provided the PDX model. Y.A.W., X. Lu, G.W., Z.L., D.C. and P.Dey provided intellectual contributions throughout the project. D.Z., Y.A.W., D.J.S. and R.A.D. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Y. Alan Wang or Ronald A. DePinho.

Reviewer Information Nature thanks W. Wei and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. 1.

    Supplementary Figures

    This file contain the Western Blots for Figures 1d, 2a, c, 3 a, b, d, e, f, g, h, i.

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    Supplementary Table 1

    CHD1 and H3K4me3 ChIP-seq overlap TSS signal annotate. The CHD1/H3K4me3-enriched TSS regions across gene promoters in PC-3 cells (only CHD1 and H3K4me3 ChIP-seq overlap genes shown).

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    Supplementary Table 2

    CHD1 ChIP-seq signal annotate. The annotated CHD1 binding regions across gene promoters in PC-3 cells.

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    Supplementary Table 3

    Alternatively expressed genes in CHD1 knockdown PC-3 cells. Fold changes of down-regulated and up-regulated genes in shCHD1 (#2 and #4) vs. control PC-3 cells are shown (Fold change >1.5). P values are calculated by t test.

  4. 4.

    Supplementary Table 4

    Alternatively expressed genes in CHD1 knockout LNCaP cells. Fold changes of down-regulated and up-regulated genes in CHD1 knockout vs. control LNCaP cells are shown (Fold change >1.5). P values are calculated by t test.

  5. 5.

    Supplementary Table 5

    Real-time PCR primers.

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    Supplementary Data

    This zipped file contains 2 Supplementary Data files.

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