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Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis

Shinichiro Kato1, Qing Yu Weng1, Megan L Insco2,3,4

  • 1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.

Cancer Discovery
|April 10, 2020
PubMed

Insights

Activating mutations and copy gains in the G9a gene drive melanoma growth and immune evasion by activating WNT signaling. Targeting G9a offers a therapeutic strategy for melanoma and other cancers.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Genomics

Background:

  • Genomic alterations in epigenetic regulators can act as oncogenes, driving cancer progression without clear genetic mutations.
  • The WNT/β-catenin pathway is frequently activated in various cancers, including melanoma.
  • The role of G9a histone methyltransferase in melanoma tumorigenesis and immune microenvironment modulation remains largely unexplored.

Purpose of the Study:

  • To identify genomic alterations in the G9a gene in human melanomas.
  • To investigate the functional consequences of G9a alterations on tumor growth and the immune microenvironment.
  • To determine if G9a is a druggable target for melanoma therapy.

Main Methods:

  • Analysis of G9a gene mutations and copy number variations in melanoma patient samples.
  • In vitro and in vivo experimental models to assess the impact of G9a on WNT pathway activation, tumor growth, and immune cell infiltration.
  • Pharmacological and genetic inhibition of G9a activity.

Main Results:

  • Recurrent activating mutations and copy gains in G9a were identified in approximately 26% of melanomas.
  • G9a gain-of-function promotes tumor growth and creates an immunologically "cold" microenvironment.
  • G9a activates the WNT pathway by suppressing the expression of the WNT antagonist DKK1.
  • Inhibition of G9a demonstrated therapeutic potential in preclinical models.

Conclusions:

  • Genomic aberrations in G9a are oncogenic drivers in melanoma, promoting tumor growth and immune suppression.
  • G9a-mediated WNT pathway activation through DKK1 repression is a key mechanism of tumorigenesis.
  • G9a represents a druggable target for melanoma treatment, with potential to convert "cold" to "hot" tumors.

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