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

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

Author information

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.

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

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