Kato S, Weng QY, Insco ML, Chen KY, Muralidhar S, Pozniak J, Diaz JMS, Drier Y, Nguyen N, Lo JA, van Rooijen E, Kemeny LV, Zhan Y, Feng Y, Silkworth W, Powell CT, Liau BB, Xiong Y, Jin J, Newton-Bishop J, Zon LI, Bernstein BE, Fisher DE. 2020. Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis. Cancer discovery. 10(7):980-997. Pubmed: 32269030 DOI:10.1158/2159-8290.CD-19-0532


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 and 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..
©2020 American Association for Cancer Research.

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Photo of Len Zon

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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