An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2019
- Source ID
- 10.1038/s41467-019-10681-4
Entities
People
- Alison Hirukawa
- Ana Cristina Vargas Calderon
- Asier Unciti-Broceta
- Carolin Temps
- Caroline L. Cooper
- Catherine R. Dufour
- Christina Selinger
- Cynthia Lavoie
- Dongmei Zuo
- Eran R Andrechek
- Ewan Millar
- Harvey W. Smith
- Ipshita Nandi
- Ivan Topisirovic
- Jane Beith
- Jonathan P. Rennhack
- Kristofferson Tandoc
- Lyndsay N. Harris
- Mark Basik
- Matthew Leibovitch
- Matthew Swiatnicki
- Morag Park
- Neil O. Carragher
- Ola Larsson
- Paul Savage
- Salendra Singh
- Sandra A. O’toole
- Vasilios Papavasiliou
- Vinay Varadan
- Vincent Giguère
- Vincent Van Hoef
- Virginie Sanguin-gendreau
- William Muller
Organizations
- Canada Research Chair
- Canadian Institutes of Health Research
- Congressionally Directed Medical Research Programs