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

Harvey W. Smith, Alison Hirukawa, Virginie Sanguin-Gendreau, Ipshita Nandi, Catherine R. Dufour, Dongmei Zuo, Kristofferson Tandoc, Matthew Leibovitch, Salendra Singh, Jonathan P. Rennhack, Matthew Swiatnicki, Cynthia Lavoie, Vasilios Papavasiliou, Carolin Temps, Neil O. Carragher, Asier Unciti-Broceta, Paul Savage, Mark Basik, Vincent van Hoef, Ola Larsson, Caroline L. Cooper, Ana Cristina Vargas Calderon, Jane Beith, Ewan Millar, Christina Selinger, Vincent Giguère, Morag Park, Lyndsay N. Harris, Vinay Varadan, Eran R. Andrechek, Sandra A. O’Toole, Ivan Topisirovic and William J. Muller ()
Additional contact information
Harvey W. Smith: McGill University
Alison Hirukawa: McGill University
Virginie Sanguin-Gendreau: McGill University
Ipshita Nandi: McGill University
Catherine R. Dufour: McGill University
Dongmei Zuo: McGill University
Kristofferson Tandoc: McGill University
Matthew Leibovitch: McGill University
Salendra Singh: Case Western University
Jonathan P. Rennhack: Michigan State University
Matthew Swiatnicki: Michigan State University
Cynthia Lavoie: McGill University
Vasilios Papavasiliou: McGill University
Carolin Temps: University of Edinburgh
Neil O. Carragher: University of Edinburgh
Asier Unciti-Broceta: University of Edinburgh
Paul Savage: McGill University
Mark Basik: Case Western University
Vincent van Hoef: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute
Ola Larsson: Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute
Caroline L. Cooper: Department of Anatomical Pathology, Pathology Queensland, Princess Alexandra Hospital
Ana Cristina Vargas Calderon: Douglass Hanly Moir Pathology
Jane Beith: Chris O’Brien Lifehouse
Ewan Millar: Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Public Hospital
Christina Selinger: Dept of Tissue Pathology and Diagnostic Oncology, Royal Prince Albert Hospital
Vincent Giguère: McGill University
Morag Park: McGill University
Lyndsay N. Harris: Case Western University
Vinay Varadan: Case Western University
Eran R. Andrechek: Michigan State University
Sandra A. O’Toole: University of Sydney
Ivan Topisirovic: McGill University
William J. Muller: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10681-4

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