1. An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
- Author
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Salendra Singh, Vasilios Papavasiliou, Catherine R. Dufour, Jane Beith, Ipshita Nandi, Eran R. Andrechek, Virginie Sanguin-Gendreau, Ewan K.A. Millar, Lyndsay Harris, Asier Unciti-Broceta, Mark Basik, Harvey W. Smith, Sandra A O'Toole, Carolin Temps, Vincent van Hoef, Vinay Varadan, Vincent Giguère, Cynthia Lavoie, Matthew R. Swiatnicki, Ola Larsson, Paul Savage, Alison Hirukawa, Kristofferson Tandoc, Jonathan P. Rennhack, Christina I. Selinger, Matthew Leibovitch, Neil O. Carragher, Ana Cristina Vargas Calderon, Ivan Topisirovic, Dongmei Zuo, Morag Park, Caroline Cooper, and William J. Muller
- Subjects
0301 basic medicine ,Carcinogenesis ,Receptor, ErbB-2 ,General Physics and Astronomy ,02 engineering and technology ,mTORC1 ,medicine.disease_cause ,Epigenesis, Genetic ,CSK Tyrosine-Protein Kinase ,Mice ,Adenosine Triphosphate ,Breast cancer ,Mice, Inbred NOD ,lcsh:Science ,Multidisciplinary ,biology ,EZH2 ,Polycomb Repressive Complex 2 ,Middle Aged ,021001 nanoscience & nanotechnology ,Cancer metabolism ,Mitochondria ,Cell biology ,src-Family Kinases ,Histone methyltransferase ,Female ,0210 nano-technology ,PRC2 ,Cell signalling ,Proto-oncogene tyrosine-protein kinase Src ,Adult ,Science ,Repressor ,Breast Neoplasms ,Mice, Transgenic ,macromolecular substances ,Mechanistic Target of Rapamycin Complex 1 ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Mammary Glands, Human ,Cancer models ,Oncogenes ,General Chemistry ,Oncogene ErbB2 ,030104 developmental biology ,Protein Biosynthesis ,biology.protein ,lcsh:Q - 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., Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours.
- Published
- 2019
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