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

Publication ,  Journal Article
Mabe, NW; Garcia, NMG; Wolery, SE; Newcomb, R; Meingasner, RC; Vilona, BA; Lupo, R; Lin, C-C; Chi, J-T; Alvarez, JV
Published in: Cell Rep
November 3, 2020

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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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

November 3, 2020

Volume

33

Issue

5

Start / End Page

108341

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Necrosis Factor-alpha
  • Transcription, Genetic
  • Risk Factors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Neoplasm Recurrence, Local
  • Necroptosis
  • Mice, Nude
  • Mammary Neoplasms, Animal
  • Inflammation
 

Citation

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Mabe, N. W., Garcia, N. M. G., Wolery, S. E., Newcomb, R., Meingasner, R. C., Vilona, B. A., … Alvarez, J. V. (2020). G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program. Cell Rep, 33(5), 108341. https://doi.org/10.1016/j.celrep.2020.108341
Mabe, Nathaniel W., Nina Marie G. Garcia, Shayna E. Wolery, Rachel Newcomb, Ryan C. Meingasner, Brittany A. Vilona, Ryan Lupo, Chao-Chieh Lin, Jen-Tsan Chi, and James V. Alvarez. “G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.Cell Rep 33, no. 5 (November 3, 2020): 108341. https://doi.org/10.1016/j.celrep.2020.108341.
Mabe NW, Garcia NMG, Wolery SE, Newcomb R, Meingasner RC, Vilona BA, et al. G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program. Cell Rep. 2020 Nov 3;33(5):108341.
Mabe, Nathaniel W., et al. “G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.Cell Rep, vol. 33, no. 5, Nov. 2020, p. 108341. Pubmed, doi:10.1016/j.celrep.2020.108341.
Mabe NW, Garcia NMG, Wolery SE, Newcomb R, Meingasner RC, Vilona BA, Lupo R, Lin C-C, Chi J-T, Alvarez JV. G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program. Cell Rep. 2020 Nov 3;33(5):108341.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

November 3, 2020

Volume

33

Issue

5

Start / End Page

108341

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Necrosis Factor-alpha
  • Transcription, Genetic
  • Risk Factors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Neoplasm Recurrence, Local
  • Necroptosis
  • Mice, Nude
  • Mammary Neoplasms, Animal
  • Inflammation