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.
Highlights
Dysregulation of histone modifications promotes carcinogenesis by altering transcription
As Src family kinase (SFK) activity has been associated with angiogenesis during development and in cancer[19,20], we examined the presence of CD31+ endothelial cells in control and c-Src-deficient tumors, finding no significant difference (Supplementary Fig. 1f)
These data show that c-Src loss causes a tumor cell-intrinsic proliferation defect that significantly impairs ErbB2-driven mammary tumorigenesis
Summary
Dysregulation of histone modifications promotes carcinogenesis by altering transcription. PRC2 exerts oncogenic effects, its overexpression may facilitate tumorigenesis in the absence of activating mutations of its components This is thought to be the case in breast cancer, where EZH2 overexpression is associated with poor prognosis[5]. Metabolic pathways are reprogrammed in cancer cells by genetic alterations in enzymes and their regulators and by aberrant signaling following activation of canonical oncogenes and inactivation of tumor suppressor genes[11]. Research in this area has focussed largely on up-regulation of aerobic glycolysis (the Warburg Effect), cancer cells can depend on ATP synthesis through mitochondrial oxidative phosphorylation (OXPHOS) to fulfill their bioenergetic requirements[11]. Given the central role of these metabolic processes in carcinogenesis, further study of their intersections with signaling and epigenetics is warranted
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