The sirtuin family in cancer

Abstract

Sirtuins are a family of protein deacylases and ADP-ribosyl-transferases, homologs to the yeast SIR2 protein. Seven sirtuin paralogs have been described in mammals, with different subcellular locations, targets, enzymatic activities, and regulatory mechanisms. All sirtuins share NAD + as substrate, placing them as central metabolic hubs with strong relevance in lifespan, metabolism, and cancer development. Much effort has been devoted to studying the roles of sirtuins in cancer, providing a wealth of data on sirtuins roles in mouse models and humans. Also, extensive data are available on the effects of pharmacological modulation of sirtuins in cancer development. Here, we present a comprehensive and organized resume of all the existing evidence linking every sirtuin with cancer development. From our analysis, we conclude that sirtuin modulation after tumor initiation results in unpredictable outcomes in most tumor types. On the contrary, all genetic and pharmacological models indicate that sirtuins activation prior to tumor initiation can constitute a powerful preventive strategy.

Energy Restriction and Colorectal Cancer: A Call for Additional Research

“…Therefore, preventing toxic accumulation of protein or organelles and oncogenic signaling through autophagy represents another defensive influence mediated by ER-based strategies against cancer and CRC [178], although different sensitivities for autophagy inhibition in CRC have been described [179]. Importantly, contradictory implications for autophagy and SIRT1 in carcinogenesis and CRC are also found, with oncogenic or tumor suppressive functions depending on the cancer type and the particular background or tumor microenvironment [174,178,180,181]. A systematic meta-analysis carried out by Zu et al also revealed that SIRT1 expression correlates with depth of invasion and predicts a poor overall survival [182].…”

Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells

“…The currently known 18 histone deacetylase enzymes (HDACs) are divided into four groups, among which sirtuin enzymes, that are homologs to the yeast SIR2 protein (Silent Information Regulator 2), comprise group III, requiring NAD + as a cofactor. They are a seven member family of protein deacylases and ADP-ribosyl-transferases with different targets, enzymatic activities, subcellular localizations, and regulatory mechanisms [ Table 1; (8,9)]. Since they are major hubs in the regulatory network of energy homeostasis and metabolism, sirtuins are potential therapeutic targets both in oncology and in the field of inborn errors of metabolism as well.…”

“…In cancer, sirtuins have both oncogenic and tumor suppressor properties, however, data are controversial at several points. As an example for emphasizing the importance of tissue microenvironment, SIRT1 has been proposed both as a tumor suppressor and as an oncogene in different types of malignancies (8). SIRT4 acts as a tumor suppressor by regulating cell metabolism and inflammation as well (10).…”

“…Elevated expression level of CPS1 would be supported by acetylation, and was associated with poor overall survival in LKB1-inactivated lung adenocarcinoma (63). SIRT5 desuccinylates and activates superoxide dismutase 1 (SOD1) (9), the oncogene serine hydroxymethyltransferase (SHMT2) (64), and pyruvate kinase M2 (PKM2) at two residues, K311 and K498 (8). Desuccinylation of PKM2 at K498 was shown to promote tumor development (8), while the role of K311 desuccinylation in cancer has not been described yet (65).…”

“…SIRT5 desuccinylates and activates superoxide dismutase 1 (SOD1) (9), the oncogene serine hydroxymethyltransferase (SHMT2) (64), and pyruvate kinase M2 (PKM2) at two residues, K311 and K498 (8). Desuccinylation of PKM2 at K498 was shown to promote tumor development (8), while the role of K311 desuccinylation in cancer has not been described yet (65). In hepatocellular carcinoma, SIRT5 was shown to keep oxidative damage below toxic levels by desuccinylating and inhibiting peroxisomal acyl-CoA oxidase 1 (ACOX1) enzyme (66).…”