Abstract
Sirtuin 6 (SIRT6) is an NAD+-dependent protein deacylase and mono-ADP-ribosyltransferase of the sirtuin family with a wide substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has beneficial effects for cellular processes such as DNA repair, metabolic regulation, and aging. On the other hand, SIRT6 has contrasting roles in cancer, acting either as a tumor suppressor or promoter in a context-specific manner. Given its central role in cellular homeostasis, SIRT6 has emerged as a promising target for the development of small-molecule activators and inhibitors possessing a therapeutic potential in diseases ranging from cancer to age-related disorders. Moreover, specific modulators allow the molecular details of SIRT6 activity to be scrutinized and further validate the enzyme as a pharmacological target. In this Perspective, we summarize the current knowledge about SIRT6 pharmacology and medicinal chemistry and describe the features of the activators and inhibitors identified so far.
Highlights
The sirtuin family is a class of enzymes that employs NAD+ as cofactor.[1]
Further investigations indicated that sirtuin 6 (SIRT6) knockout in MEFs leads to tumorigenesis without activation of known oncogenes, and deletion of SIRT6 in vivo correlates with an increased number, size, and aggressiveness of tumors (Figure 4).[8,11]
This study shows that small-molecule-mediated SIRT6 inhibition mimics the effects of SIRT6 knockdown
Summary
The sirtuin family is a class of enzymes that employs NAD+ as cofactor.[1]. initially classified as class III HDACs, sirtuins (SIRTs) are capable of catalyzing different reactions and possess a wide range of substrates far beyond histones.[2]. DNA damage and cell cycle dysregulation are two of the most important hallmarks of cancer; it comes with no surprise that SIRT6 has been regarded as a tumor suppressor, as indicated by early studies in knockout mice showing genomic instability.[6] Further investigations indicated that SIRT6 knockout in MEFs leads to tumorigenesis without activation of known oncogenes, and deletion of SIRT6 in vivo correlates with an increased number, size, and aggressiveness of tumors (Figure 4).[8,11] The tumor-suppressor role of SIRT6 was associated with the suppression of glycolytic genes crucial for the Warburg effect, a metabolic shift common in cancer cells where ATP is obtained mostly through glycolysis rather than mitochondrial oxidative phosphorylation, in order to generate immediate energy to support fast proliferation and related cellular processes.[58] These genes, including the glucose transporter-1 (GLUT1), lactate dehydrogenase (LDH), phosphofructokinase-1 (PFK1), and pyruvate dehydrogenase kinase-1 (PDK1), are regulated by the hypoxia-inducible factor 1α (HIF-1α), which is corepressed by SIRT6.59 SIRT6 deacetylates pyruvate kinase M2 (PKM2), a nuclear isozyme that enhances aerobic glycolysis even under hypoxia conditions and promotes tumor growth. It reduced the blood glucose content in a mouse model of type 2 diabetes, demonstrating promising lead-like properties
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