The multifaceted functions of sirtuins in cancer

Sirtuins are NAD+-dependent enzymes that modulate the activities of target proteins, mediate changes in the metabolic status of cells and regulate diseases of ageing, including neurodegeneration, diabetes, cardiovascular diseases and cancer.Sirtuin 1 (SIRT1) was the first sirtuin to be shown to be involved in cancer. It was demonstrated that SIRT1 represses p53-mediated tumour suppression. Since this finding, SIRT1 has been shown to have both tumour-suppressive and oncogenic roles, depending on the type and stage of cancer.The mitochondrial sirtuin SIRT3 regulates levels of reactive oxygen species (ROS). Loss of SIRT3 results in increased levels of ROS, with subsequent activation of hypoxia-inducible factor 1α (HIF1α) and increased expression of HIF1 target genes, including glycolysis and angiogenesis genes, which favour tumour growth.The mitochondrial sirtuin SIRT4 regulates glutamine metabolism by inhibiting glutamate dehydrogenase (GDH), the rate-limiting enzyme in glutaminolysis. Loss of SIRT4 leads to increased glutamine catabolism, a pathway that promotes tumour growth.The chromatin-bound sirtuin SIRT6 regulates cancer metabolism and inflammation by acting as a co-repressor for HIF1α, MYC and nuclear factor-κB (NF-κB). Loss of SIRT6 results in increased expression of glycolysis, glutaminolysis and ribosomal genes, all of which favour proliferation and tumorigenesis.SIRT1 and SIRT6 promote genomic stability by regulating both single- and double-strand DNA break-repair pathways.