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INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer

Oncogene volume 36, pages 1430–1439 (2017)Cite this article

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Abstract

Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC). Ino80, the SWI/SNF ATPase in the complex, is highly expressed in NSCLC cells compared with normal lung epithelia cells. Further, its expression, as well as that of another subunit Ino80B, negatively correlates with disease prognosis in lung cancer patients. Functionally, INO80 silencing inhibits NSCLC cell proliferation and anchorage-independent growth in vitro and tumor formation in mouse xenografts. It occupies enhancer regions near lung cancer-associated genes, and its occupancy correlates with increased genome accessibility and enhanced expression of downstream genes. Together, our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex.

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References

  1. Bender E . Epidemiology: the dominant malignancy. Nature 2014; 513: S2–S3.

    Article  CAS  PubMed  Google Scholar 

  2. Lennon FE, Cianci GC, Cipriani NA, Hensing TA, Zhang HJ, Chen CT et al. Lung cancer-a fractal viewpoint. Nat Rev Clin Oncol 2015; 12: 664–675.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK . Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 2014; 14: 535–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF . Management of non-small-cell lung cancer: recent developments. Lancet 2013; 382: 709–719.

    Article  CAS  PubMed  Google Scholar 

  5. Viktorsson K, Lewensohn R, Zhivotovsky B . Systems biology approaches to develop innovative strategies for lung cancer therapy. Cell Death Dis 2014; 5: e1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M . Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 2012; 11: 384–400.

    Article  CAS  PubMed  Google Scholar 

  7. Belinsky SA . Unmasking the lung cancer epigenome. Annu Rev Physiol 2015; 77: 453–474.

    Article  CAS  PubMed  Google Scholar 

  8. Jakopovic M, Thomas A, Balasubramaniam S, Schrump D, Giaccone G, Bates SE . Targeting the epigenome in lung cancer: expanding approaches to epigenetic therapy. Front Oncol 2013; 3: 261.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA . Epigenetic therapy in lung cancer. Front Oncol 2013; 3: 135.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hargreaves DC, Crabtree GR . ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res 2011; 21: 396–420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Narlikar GJ, Sundaramoorthy R, Owen-Hughes T . Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 2013; 154: 490–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Helming KC, Wang X, Roberts CW . Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 2014; 26: 309–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kadoch C, Crabtree GR . Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv 2015; 1: e1500447.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Masliah-Planchon J, Bieche I, Guinebretiere JM, Bourdeaut F, Delattre O . SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol 2015; 10: 145–171.

    Article  CAS  PubMed  Google Scholar 

  15. Conaway RC, Conaway JW . The INO80 chromatin remodeling complex in transcription, replication and repair. Trends Biochem Sci 2009; 34: 71–77.

    Article  CAS  PubMed  Google Scholar 

  16. Morrison AJ, Shen X . Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes. Nat Rev Mol Cell Biol 2009; 10: 373–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Watanabe S, Peterson CL . The INO80 family of chromatin-remodeling enzymes: regulators of histone variant dynamics. Cold Spring Harb Symp Quant Biol 2010; 75: 35–42.

    Article  CAS  PubMed  Google Scholar 

  18. Wang L, Du Y, Ward JM, Shimbo T, Lackford B, Zheng X et al. INO80 facilitates pluripotency gene activation in embryonic stem cell self-renewal, reprogramming, and blastocyst development. Cell Stem Cell 2014; 14: 575–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40: 499–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim J, Orkin SH . Embryonic stem cell-specific signatures in cancer: insights into genomic regulatory networks and implications for medicine. Genome Med 2011; 3: 75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY . Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2008; 2: 333–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stewart DJ . Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst 2014; 106: djt356.

    Article  PubMed  Google Scholar 

  23. Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, Xue YY et al. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin invest 1998; 102: 465–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kolluri SK, Bruey-Sedano N, Cao X, Lin B, Lin F, Han YH et al. Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol 2003; 23: 8651–8667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Linxweiler M, Linxweiler J, Barth M, Benedix J, Jung V, Kim YJ et al. Sec62 bridges the gap from 3q amplification to molecular cell biology in non-small cell lung cancer. Am J Pathol 2012; 180: 473–483.

    Article  CAS  PubMed  Google Scholar 

  26. Baykara O, Bakir B, Buyru N, Kaynak K, Dalay N . Amplification of chromosome 8 genes in lung cancer. J Cancer 2015; 6: 270–275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kramer A, Green J, Pollard J Jr, Tugendreich S . Causal analysis approaches in Ingenuity pathway analysis. Bioinformatics 2014; 30: 523–530.

    Article  PubMed  Google Scholar 

  28. El-Telbany A, Ma PC . Cancer genes in lung cancer: racial disparities: are there any? Genes Cancer 2012; 3: 467–480.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Job B, Bernheim A, Beau-Faller M, Camilleri-Broet S, Girard P, Hofman P et al. Genomic aberrations in lung adenocarcinoma in never smokers. PloS One 2010; 5: e15145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Papamichos-Chronakis M, Watanabe S, Rando OJ, Peterson CL . Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. Cell 2011; 144: 200–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Watanabe S, Radman-Livaja M, Rando OJ, Peterson CL . A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme. Science 2013; 340: 195–199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gaspar-Maia A, Alajem A, Meshorer E, Ramalho-Santos M . Open chromatin in pluripotency and reprogramming. Nat Rev Mol Cell Biol 2011; 12: 36–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu G, Schones DE, Cui K, Ybarra R, Northrup D, Tang Q et al. Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1. Genome Res 2011; 21: 1650–1658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Laurette P, Strub T, Koludrovic D, Keime C, Le Gras S, Seberg H et al. Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells. eLife 2015; 4 doi:10.7554/eLife.06857.

  35. Min JN, Tian Y, Xiao Y, Wu L, Li L, Chang S . The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability. Cell Res 2013; 23: 1396–1413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han L, Diao L, Yu S, Xu X, Li J, Zhang R et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 2015; 28: 515–528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the NIEHS Animal, Epigenomics and Bioinformatics core facilities for assistance with various techniques and experiments. This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Z01ES102745 (to GH) and by National Institutes of Health Grants CA042978 and CA161494 (to ADC).

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Author notes

  1. S Zhang, B Zhou and L Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China

    S Zhang & L Chen

  2. Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    B Zhou & A D Cox

  3. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    B Zhou & L Wang

  4. Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    L Wang, P Li & G Hu

  5. Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    B D Bennett & D C Fargo

  6. Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    R Snyder & S Garantziotis

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  1. S Zhang
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Correspondence to L Chen or G Hu.

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Zhang, S., Zhou, B., Wang, L. et al. INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene 36, 1430–1439 (2017). https://doi.org/10.1038/onc.2016.311

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  • DOI: https://doi.org/10.1038/onc.2016.311

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