Targeting aberrant cancer metabolism – The role of sirtuins

Abstract

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.

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…However, one can speculate that stress-induction and/or activation of acetyltransferase p300/CBP was involved, or possibly downregulation of a p65 deacetylase such as Sirt1 (75). These different possibilities will be assessed in our ongoing studies.…”

The inhibition of c-MYC transcription factor modulates the expression of glycolytic and glutaminolytic enzymes in FaDu hypopharyngeal carcinoma cells

“…Moreover, it has been proposed that SIRT6 functions as a corepressor of HIF-1a and c-MYC by deacetylating H3K9 and H3K56 at HIF-1a and c-MYC target gene promoters, respectively. 13,24 Since SIRT6 is downregulated in many tumors, including HNSCCs, SIRT6 upregulation may be expected to reverse the tumorigenic metabolic profile. To test this hypothesis, we used 2 stilbene derivatives, resveratrol and its methoxy-analogue, DMU-212, as possible activators since resveratrol was previously described as an activator of SIRT1.…”

“…Sirtuins have recently emerged as important regulators of energy metabolism in mammalian cells. 13 Sirtuins (SIRTs) belong to Class III of the histone deacetylase (HDACs) family and are the only HDACs that require NAD + for their proper enzymatic activity. 14 Histone acetylation is known to promote the local transcriptional activity of chromatin, whereas histone deacetylases, by removing acetyl groups, lead to the formation of tightly packed and transcriptionally inactive heterochromatin.…”

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

“…Post-translationally, G6PD is modified by lysine acetylation, phosphorylation, ubiquitination and O-GlcNAcylation34353637. We previously found that G6PD is deacetylated and activated by SIRT238, which led us to explore the possibility of targeting SIRT2 to suppress G6PD and leukaemia394041. SIRT2-mediated deacetylation of G6PD sustained NADPH production and promoted cell proliferation across different subtypes of AML.…”