Histone deacetylases in cancer metabolic reprogramming

Abstract

Cancer cells undergo extensive metabolic reprogramming to sustain rapid proliferation and adapt to heterogeneous tumour microenvironments. These metabolic alterations are tightly linked to epigenetic regulation, which reshapes gene expression and cellular signalling mechanisms. Among epigenetic regulators, histone deacetylases (HDACs) have emerged as key modulators of cancer metabolic reprogramming. Along with their canonical roles in histone deacetylation, HDACs regulate non-histone substrates, including metabolic enzymes and transcription factors, thereby coordinating transcriptional and metabolic programmes. In this review, we summarize current insights into HDAC-mediated regulation of glucose, lipid and amino acid metabolism in cancer and discuss the metabolic mechanisms underlying the anticancer effects of HDAC inhibitors. Collectively, we propose an integrated framework in which HDACs function as central regulators of cancer metabolic reprogramming. We highlight the limitations of HDAC inhibitor studies and discuss the emerging importance of isoform-specific HDAC functions in reprogramming cancer-specific metabolic dependencies and therapeutic strategies. Histone deacetylases (HDACs) are crucial in epigenetic regulation, influencing gene expression and cellular metabolism. This review explores the roles of HDACs in cancer metabolic reprogramming, particularly in glucose, lipid and amino acid metabolism. The authors discuss how HDACs, through deacetylation, regulate both histone and non-histone proteins, impacting processes such as glycolysis, the Warburg effect and fatty-acid oxidation. They highlight significant findings, such as the role of HDAC1 in controlling glucose and lipid metabolisms and the regulation of glycolysis and glutamine metabolism in cancer by HDAC6. These insights underscore the potential of HDACs as therapeutic targets, with HDAC inhibitors already in clinical use for cancer treatment. The review suggests that developing isoform-specific HDAC inhibitors could enhance therapeutic precision, particularly in targeting cancer’s metabolic dependencies, pointing towards future research directions in cancer metabolism and epigenetics. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.