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

AI Article Synopsis

  • * The WNT/β-catenin pathway is significantly affected by G9a abnormalities, as G9a suppresses the WNT antagonist DKK1, contributing to tumor development.
  • * Targeting mutated or amplified G9a could be an effective therapeutic strategy, as studies show it can promote a more immune-responsive "hot" tumor environment in melanoma and other cancers.

Article 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 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..

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334057PMC
http://dx.doi.org/10.1158/2159-8290.CD-19-0532DOI Listing

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