G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.

Journal Article (Journal Article)

Dysregulated gene expression is a common feature of cancer and may underlie some aspects of tumor progression, including tumor relapse. Here, we show that recurrent mammary tumors exhibit global changes in gene expression and histone modifications and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including tumor necrosis factor (TNF), through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that G9a-mediated silencing of pro-necroptotic proteins is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.

Full Text

Duke Authors

Cited Authors

  • Mabe, NW; Garcia, NMG; Wolery, SE; Newcomb, R; Meingasner, RC; Vilona, BA; Lupo, R; Lin, C-C; Chi, J-T; Alvarez, JV

Published Date

  • November 3, 2020

Published In

Volume / Issue

  • 33 / 5

Start / End Page

  • 108341 -

PubMed ID

  • 33147463

Pubmed Central ID

  • 33147463

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2020.108341

Language

  • eng

Conference Location

  • United States