MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

William B Tu; Yu-Jia Shiah; Corey Lourenco; Peter J Mullen; Dharmendra Dingar; Cornelia Redel; Aaliya Tamachi; Wail Ba-Alawi; Ahmed Aman; Rima Al-Awar; David W Cescon; Benjamin Haibe-Kains; Cheryl H Arrowsmith; Brian Raught; Paul C Boutros; Linda Z Penn

doi:10.1016/j.ccell.2018.09.001

MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

Cancer Cell. 2018 Oct 8;34(4):579-595.e8. doi: 10.1016/j.ccell.2018.09.001.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, Toronto, ON M5G1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
² Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
³ Princess Margaret Cancer Centre, Toronto, ON M5G1L7, Canada.
⁴ Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
⁵ Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S1A8, Canada.
⁶ Princess Margaret Cancer Centre, Toronto, ON M5G1L7, Canada; Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON M5G2C4, Canada.
⁷ Princess Margaret Cancer Centre, Toronto, ON M5G1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada; Structural Genomics Consortium, Toronto, ON M5G1L7, Canada.
⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S1A8, Canada.
⁹ Princess Margaret Cancer Centre, Toronto, ON M5G1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada. Electronic address: linda.penn@uhnresearch.ca.

PMID: 30300580
DOI: 10.1016/j.ccell.2018.09.001

Abstract

MYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.

Keywords: BioID; G9a; MYC; breast cancer; epigenetic therapy; histone methylation; transcriptional repression.

Publication types

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

MeSH terms

Animals
Carcinogenesis / genetics*
Cell Line, Tumor
Epigenesis, Genetic / genetics
Gene Expression / genetics*
Histocompatibility Antigens / genetics
Histone Methyltransferases / genetics*
Histone-Lysine N-Methyltransferase / genetics
Humans
Mice
Promoter Regions, Genetic / genetics
Transcription Factors / genetics*

Substances

Histocompatibility Antigens
Transcription Factors
Histone Methyltransferases
Histone-Lysine N-Methyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding