2. Academic Validation
  3. An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis

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

  • Nat Commun. 2019 Jul 1;10(1):2901. doi: 10.1038/s41467-019-10681-4.
Harvey W Smith 1 2,  Alison Hirukawa 1 2,  Virginie Sanguin-Gendreau 1 2,  Ipshita Nandi 1 2,  Catherine R Dufour 1 2,  Dongmei Zuo 1 2,  Kristofferson Tandoc 3,  Matthew Leibovitch 3,  Salendra Singh 4,  Jonathan P Rennhack 5,  Matthew Swiatnicki 5,  Cynthia Lavoie 1 2,  Vasilios Papavasiliou 1 2,  Carolin Temps 6,  Neil O Carragher 6,  Asier Unciti-Broceta 6,  Paul Savage 1 7,  Mark Basik 4 7 8,  Vincent van Hoef 9,  Ola Larsson 9,  Caroline L Cooper 10 11,  Ana Cristina Vargas Calderon 12,  Jane Beith 13 14,  Ewan Millar 15 16 17,  Christina Selinger 18,  Vincent Giguère 1 2 7 19,  Morag Park 1 2 7 19,  Lyndsay N Harris 4 20,  Vinay Varadan 4,  Eran R Andrechek 5,  Sandra A O'Toole 14 21,  Ivan Topisirovic 3 19,  William J Muller 22 23
Affiliations

Affiliations

  • 1 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 2 Department of Biochemistry, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 3 Lady Davis Institute for Medical Research, McGill University, Montréal, QC, H3T 1E2, Canada.
  • 4 Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, 44145, USA.
  • 5 Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
  • 6 Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XR, UK.
  • 7 Department of Medicine, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 8 Department of Surgery, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 9 Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute, Stockholm, 171 76, Sweden.
  • 10 Department of Anatomical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
  • 11 PA Southside Clinical School, School of Medicine, University of Queensland, Brisbane, QLD, 4102, Australia.
  • 12 Douglass Hanly Moir Pathology, Macquarie Park, NSW, 2113, Australia.
  • 13 Chris O'Brien Lifehouse, Camperdown, NSW, 2050, Australia.
  • 14 Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
  • 15 Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Public Hospital, Kogarah, NSW, 2217, Australia.
  • 16 School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, NSW, 2560, Australia.
  • 17 Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia.
  • 18 Dept of Tissue Pathology and Diagnostic Oncology, Royal Prince Albert Hospital, Camperdown, NSW, 2050, Australia.
  • 19 Department of Oncology, McGill University, Montréal, QC, H3A 1A3, Canada.
  • 20 Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Rockville, MD, 20890, USA.
  • 21 The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.
  • 22 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada. william.muller@mcgill.ca.
  • 23 Department of Biochemistry, McGill University, Montréal, QC, H3A 1A3, Canada. william.muller@mcgill.ca.
PMID: 31263101 DOI: 10.1038/s41467-019-10681-4
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.

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