Targeting aberrant cancer metabolism - The role of sirtuins

Cancer cells, as opposed to normal cells, generate energy by increasing aerobic glycolysis, which is a phenomenon called “the Warburg effect”. An altered energy metabolism supporting continuous cell growth and proliferation was pointed to as the new “hallmark” of cancer cells. Several hypotheses have been proposed to explain the maintenance of this seemingly wasteful catabolic state. The epigenetic mechanisms which depend on the covalent modifications of both DNA and histones have recently emerged as important players in the regulation of glucose metabolism. The sirtuin family of histone deacetylases has emerged as important regulators of diverse physiological and pathological events, including cancer metabolism. Sirtuins 1-7 (SIRT1-7) belong to class III of histone deacetylase enzymes which are dependent on NAD+ for activity. It was recently demonstrated that SIRT6 is a tumor suppressor that modulates aerobic glycolysis by repressing HIF1 transcription. Members of this family of enzymes are considered promising pharmaceutical targets for cancer treatment. This review highlights the major functions of sirtuins in relation to cancer metabolism and the possibilities of their activation and inhibition by small molecule drugs.