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; William J Muller

doi:10.1038/s41467-019-10681-4

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.

Authors

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 Tandoc³, Matthew Leibovitch³, Salendra Singh⁴, Jonathan P Rennhack⁵, Matthew Swiatnicki⁵, Cynthia Lavoie^{1

2}, Vasilios Papavasiliou^{1

2}, Carolin Temps⁶, Neil O Carragher⁶, Asier Unciti-Broceta⁶, Paul Savage^{1

7}, Mark Basik^{4

7

8}, Vincent van Hoef⁹, Ola Larsson⁹, Caroline L Cooper^{10

11}, Ana Cristina Vargas Calderon¹², Jane Beith^{13

14}, Ewan Millar^{15

16

17}, Christina Selinger¹⁸, Vincent Giguère^{1

2

7

19}, Morag Park^{1

2

7

19}, Lyndsay N Harris^{4

20}, Vinay Varadan⁴, Eran R Andrechek⁵, Sandra A O'Toole^{14

21}, Ivan Topisirovic^{3

19}, William J Muller^{22

23}

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. [email protected].
²³ Department of Biochemistry, McGill University, Montréal, QC, H3A 1A3, Canada. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenosine Triphosphate / metabolism
Adult
Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
CSK Tyrosine-Protein Kinase
Carcinogenesis
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Epigenesis, Genetic*
Female
Humans
Mammary Glands, Human / metabolism
Mammary Glands, Human / pathology
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Inbred NOD
Mice, Transgenic
Middle Aged
Mitochondria / genetics
Mitochondria / metabolism
Polycomb Repressive Complex 2 / genetics*
Polycomb Repressive Complex 2 / metabolism
Protein Biosynthesis
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*
src-Family Kinases / genetics
src-Family Kinases / metabolism*

Substances

Adenosine Triphosphate
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2
ERBB2 protein, human
Receptor, ErbB-2
CSK Tyrosine-Protein Kinase
src-Family Kinases
CSK protein, human
Mechanistic Target of Rapamycin Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding