An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic 2 reprogramming and mammary tumourigenesis

Harvey W Smith, Alison Hirukawa, Virginie Sanguin-Gendreau, Ipshita Nandi, Catherine R Dufour, Dongmei Zuo, Kristofferson Tandoc, Matthew Leibovitch, Salendra Singh, Jonathan Rennhack, Matthew Swiatnicki, Cynthia Lavoie, Vasilios Papavasiliou, Carolin Temps, Neil Carragher, Asier Unciti-Broceta, Paul Savage, Mark Basik, Vincent van Hoef, Ola LarssonCaroline L Cooper, Ana Cristina Vargas Calderon, Jane Beith, Ewan Millar, Christina Selinger, Vincent Giguère, Morag Park, Lyndsey R Harris, Vinay Varadan, Eran Andrechek, Sandra A O'Toole, Ivan Topisirovic, William J Muller

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer.
Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1(mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
Original languageEnglish
JournalNature Communications
DOIs
Publication statusPublished - 1 Jul 2019

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