Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis.

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.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

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,Fish

doi

10.1158/2159-8290.CD-19-0532

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

980-997

issue

7

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-19-0532

journal_volume

10

pub_type

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