Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    , , , & Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997)

  2. 2.

    et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005)

  3. 3.

    et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337–342 (2012)

  4. 4.

    et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res . 57, 4997–5000 (1997)

  5. 5.

    et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003)

  6. 6.

    , & Synthetic lethal vulnerabilities of cancer. Annu. Rev. Pharmacol. Toxicol . 55, 513–531 (2015)

  7. 7.

    et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005)

  8. 8.

    et al. Cancer vulnerabilities unveiled by genomic loss. Cell 150, 842–854 (2012)

  9. 9.

    et al. High-throughput oncogene mutation profiling in human cancer. Nat. Genet . 39, 347–351 (2007)

  10. 10.

    , , & Mutual exclusivity analysis identifies oncogenic network modules. Genome Res . 22, 398–406 (2012)

  11. 11.

    et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med . 1, 315–322 (2009)

  12. 12.

    & Therapeutic targeting of cancers with loss of PTEN function. Curr. Drug Targets 15, 65–79 (2014)

  13. 13.

    et al. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 26, 163–176 (2014)

  14. 14.

    et al. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene 31, 4164–4170 (2012)

  15. 15.

    et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res . 73, 2795–2805 (2013)

  16. 16.

    Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015)

  17. 17.

    et al. Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res . 75, 1021–1034 (2015)

  18. 18.

    et al. The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Curr. Biol . 9, 207–210 (1999)

  19. 19.

    , , , & A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(β-TRCP). Genes Dev . 24, 72–85 (2010)

  20. 20.

    et al. SCF(β-TRCP) and phosphorylation dependent ubiquitination of IκBα catalyzed by Ubc3 and Ubc4. Oncogene 19, 3529–3536 (2000)

  21. 21.

    , & The many faces of β-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene 23, 2028–2036 (2004)

  22. 22.

    et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1181–1185 (2005)

  23. 23.

    et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 460, 863–868 (2009)

  24. 24.

    & Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol . 12, 715–723 (2011)

  25. 25.

    , , , & Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001)

  26. 26.

    et al. Inhibition of NF-κB signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. Oncogene 34, 3700–3710 (2015)

  27. 27.

    et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011)

  28. 28.

    et al. Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci. Transl. Med . 6, 252ra122 (2014)

  29. 29.

    et al. A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol. Cell 47, 810–822 (2012)

  30. 30.

    et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst . 1, 417–425 (2015)

Download references

Acknowledgements

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.).

Author information

Author notes

    • Xin Lu
    •  & Guocan Wang

    These authors contributed equally to this work.

Affiliations

  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

Authors

  1. Search for Di Zhao in:

  2. Search for Xin Lu in:

  3. Search for Guocan Wang in:

  4. Search for Zhengdao Lan in:

  5. Search for Wenting Liao in:

  6. Search for Jun Li in:

  7. Search for Xin Liang in:

  8. Search for Jasper Robin Chen in:

  9. Search for Sagar Shah in:

  10. Search for Xiaoying Shang in:

  11. Search for Ming Tang in:

  12. Search for Pingna Deng in:

  13. Search for Prasenjit Dey in:

  14. Search for Deepavali Chakravarti in:

  15. Search for Peiwen Chen in:

  16. Search for Denise J. Spring in:

  17. Search for Nora M. Navone in:

  18. Search for Patricia Troncoso in:

  19. Search for Jianhua Zhang in:

  20. Search for Y. Alan Wang in:

  21. Search for Ronald A. DePinho in:

Contributions

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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

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

Excel files

  1. 1.

    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).

  2. 2.

    Supplementary Table 2

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

  3. 3.

    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.

Zip files

  1. 1.

    Supplementary Data

    This zipped file contains 2 Supplementary Data files.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature21357

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.