Journal
MOLECULAR CANCER RESEARCH
Volume 14, Issue 2, Pages 173-184Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-15-0263
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Funding
- NIH [R01s CA164492, CA176843, CA164492-S1]
- Grant Achatz and the Alinea team
- Susan G. Komen Postdoctoral Fellowship [KG101224]
- [P50 GM086145]
- [Ludwig Center for Metastasis Research]
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Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transfer-ase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including alpha-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability. (C) 2015 AACR.
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