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

• Published in: Cell reports (Cambridge) Vol. 33; no. 5; p. 108341
• Main Authors: Mabe, Nathaniel W., Garcia, Nina Marie G., Wolery, Shayna E., Newcomb, Rachel, Meingasner, Ryan C., Vilona, Brittany A., Lupo, Ryan, Lin, Chao-Chieh, Chi, Jen-Tsan, Alvarez, James V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-11-2020; Elsevier
• Subjects: Animals; breast cancer; Cell Death; Cell Survival; collateral sensitivity; Epigenesis, Genetic; epigenetics; Female; G9a; Gene Expression Regulation, Neoplastic; Gene Silencing; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - metabolism; Inflammation - pathology; Mammary Neoplasms, Animal - enzymology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Mice, Nude; Necroptosis; Neoplasm Recurrence, Local - pathology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; recurrence; RIPK3; Risk Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha - metabolism; Tumor Suppressor Protein p53 - metabolism; recurrence; RIPK3; breast cancer; collateral sensitivity; G9a; epigenetics; necroptosis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108341

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.
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•Recurrent tumors show global changes in gene expression and histone modifications•Recurrent tumors are dependent on activity of the histone methyltransferase G9a•G9a represses pro-inflammatory genes in recurrent tumors•G9a inhibition in recurrent tumors leads to induction of necroptotic cell death
Mabe et al. show that the histone methyltransferase G9a promotes breast cancer recurrence. They find that G9a functions to repress pro-inflammatory genes in recurrent tumors and demonstrate that elevated RIPK3 expression in recurrent tumor cells sensitizes these cells to necroptosis following G9a inhibition.