Glycolytic metabolism influences global chromatin structure
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Xue-Song Liu, John B. Little, Zhi-Min Yuan
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Zhi-Min Yuan, e-mail: [email protected]
Keywords: glycolysis, acetylation, chromatin structure, chemosensitivity
Received: September 29, 2014 Accepted: December 15, 2014 Published: January 13, 2015
Metabolic rewiring, specifically elevated glycolytic metabolism is a hallmark of cancer. Global chromatin structure regulates gene expression, DNA repair, and also affects cancer progression. But the interrelationship between tumor metabolism and chromatin architecture remain unclear. Here we show that increased glycolysis in cancer cells promotes an open chromatin configuration. Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure. This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state. Interestingly, glycolysis inhibition-induced chromatin condensation impeded DNA repair efficiency leading to increased sensitivity of cancer cells to DNA damage drugs, which may represent a novel molecular mechanism that can be exploited for cancer therapy.
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