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MYC interacts with the G9a histone methyltransferase to control transcriptional repression in cancer

ABSTRACT: MYC is a master regulator of transcriptional activation and repression that mediates diverse physiological and disease functions, including hematopoiesis, aging, and oncogenesis, yet its essential co-regulators remain unclear. We demonstrate that MYC interacts with and regulates the G9a H3K9 methyltransferase complex to control transcriptional repression in cancer. Inhibiting G9a hinders MYC binding, shifts repressive epigenetic locales to an active state, and de-represses gene expression to antagonize MYC-dependent cellular processes. MYC requires MYC Box II region for its interaction with G9a, providing a mechanism for this region essential for transcriptional repression. In treatment models of MYC-dependent basal breast cancer, genetically inhibiting G9a decreases tumour growth. Anti-proliferative sensitivity to G9a small molecule inhibitors correlates with sensitivity to MYC knockdown and associates with the basal subtype. Our findings illustrate an epigenetic model of MYC-mediated transcriptional repression in driving oncogenesis and establishes G9a as a therapeutic vulnerability in MYC-driven cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100335 | GEO | 2018/10/08

REPOSITORIES: GEO

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MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

Project description:MYC is an oncogenic driver that regulates transcriptional activation and repression, yet molecular mechanisms of MYC 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 to antagonize cellular transformation. 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. In breast cancer, anti-proliferative sensitivity to G9a pharmacological inhibition associates with MYC sensitivity and the basal subtype. Inhibiting G9a in vivo suppresses MYC-dependent basal breast tumor growth. Our findings reveal G9a as an epigenetic regulator of MYC-mediated transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.

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MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

Project description:MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis

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Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (array)

Project description:Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumors . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis. P493 cells were stably infected with the following viruses: pLKO shControl and pLKO shTERT.

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Role of the histone methylase G9a in pancreatic carcinogenesis

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Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (ChIP-Seq)

Project description:Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumours . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis. ChIP was performed using anti-MYC (sc-764) in primary lymphoma cells from Eµ-Myc;Tert -/- mice, Eµ-Myc;Tert +/+ mice, or in P493 cells treated with shTert, P493 shTerc and shControl.

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2013-02-01 | E-GEOD-41456 | biostudies-arrayexpress

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Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.

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Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [RNA-seq]

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