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Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis

Shinichiro Kato, Qing Yu Weng, Megan L. Insco, Kevin Y. Chen, Sathya Muralidhar, Joanna Pozniak, Joey Mark S. Diaz, Yotam Drier, Nhu Nguyen, Jennifer A. Lo, Ellen van Rooijen, Lajos V. Kemeny, Yao Zhan, Yang Feng, Whitney Silkworth, C. Thomas Powell, Brian B. Liau, Yan Xiong, Jian Jin, Julia Newton-Bishop, Leonard I. Zon, Bradley E. Bernstein and David E. Fisher
Shinichiro Kato
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Qing Yu Weng
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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  • ORCID record for Qing Yu Weng
Megan L. Insco
2Howard Hughes Medical Institute, Chevy Chase, Maryland.
3Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
4Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts.
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Kevin Y. Chen
2Howard Hughes Medical Institute, Chevy Chase, Maryland.
3Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
4Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts.
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Sathya Muralidhar
5Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
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Joanna Pozniak
5Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
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Joey Mark S. Diaz
5Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
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Yotam Drier
6Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts.
7Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
8Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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  • ORCID record for Yotam Drier
Nhu Nguyen
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Jennifer A. Lo
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Ellen van Rooijen
2Howard Hughes Medical Institute, Chevy Chase, Maryland.
3Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Lajos V. Kemeny
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Yao Zhan
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Yang Feng
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Whitney Silkworth
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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  • ORCID record for Whitney Silkworth
C. Thomas Powell
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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Brian B. Liau
9Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts.
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Yan Xiong
10Mount Sinai Center for Therapeutics Discovery, Department of Pharmaceutical Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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Jian Jin
10Mount Sinai Center for Therapeutics Discovery, Department of Pharmaceutical Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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Julia Newton-Bishop
5Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
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Leonard I. Zon
2Howard Hughes Medical Institute, Chevy Chase, Maryland.
3Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Bradley E. Bernstein
6Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts.
7Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
8Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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David E. Fisher
1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
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  • For correspondence: dfisher3@mgh.harvard.edu
DOI: 10.1158/2159-8290.CD-19-0532 Published July 2020
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Abstract

Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.

Significance: Oncogenic G9a abnormalities drive tumorigenesis and the “cold” immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore “hot” tumor immune microenvironments.

This article is highlighted in the In This Issue feature, p. 890

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:980–97

  • Received May 7, 2019.
  • Revision received February 5, 2020.
  • Accepted April 3, 2020.
  • Published first April 8, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (7)
July 2020
Volume 10, Issue 7
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Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis
Shinichiro Kato, Qing Yu Weng, Megan L. Insco, Kevin Y. Chen, Sathya Muralidhar, Joanna Pozniak, Joey Mark S. Diaz, Yotam Drier, Nhu Nguyen, Jennifer A. Lo, Ellen van Rooijen, Lajos V. Kemeny, Yao Zhan, Yang Feng, Whitney Silkworth, C. Thomas Powell, Brian B. Liau, Yan Xiong, Jian Jin, Julia Newton-Bishop, Leonard I. Zon, Bradley E. Bernstein and David E. Fisher
Cancer Discov July 1 2020 (10) (7) 980-997; DOI: 10.1158/2159-8290.CD-19-0532

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Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis
Shinichiro Kato, Qing Yu Weng, Megan L. Insco, Kevin Y. Chen, Sathya Muralidhar, Joanna Pozniak, Joey Mark S. Diaz, Yotam Drier, Nhu Nguyen, Jennifer A. Lo, Ellen van Rooijen, Lajos V. Kemeny, Yao Zhan, Yang Feng, Whitney Silkworth, C. Thomas Powell, Brian B. Liau, Yan Xiong, Jian Jin, Julia Newton-Bishop, Leonard I. Zon, Bradley E. Bernstein and David E. Fisher
Cancer Discov July 1 2020 (10) (7) 980-997; DOI: 10.1158/2159-8290.CD-19-0532
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