Sorting out functions of sirtuins in cancer

Abstract

The sirtuins (SIRT 1-7) comprise a family of NAD+ dependent protein modifying enzymes with activities in lysine deacetylation, ADP-ribosylation, and/or deacylation. These enzymes are involved in the cell’s stress response systems and in regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins play complex roles in both promoting and/or suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional loss of sirtuin genes, particularly SIRT1, involved in maintaining genome integrity and DNA repair will promote tumorigenesis due to genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cell’s genome maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions.

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

“…Both tumor-suppressive and tumor-promoting functions have been attributed to Sirt1 and Sirt2 (31,47,48). The common view, supported by knock-out experiments in mice, is that sirtuins can delay tumor formation by maintaining genome integrity (20).…”

“…Increased AKT activation is a prominent factor in many human cancers, suggesting that Sirt2 and Sirt1 overexpression could also hold tumor-promoting functions by their effect on AKT activation. In this regard, both Sirt1 and Sirt2 overexpression have been observed in multiple human cancers (31,48). Our work suggests that whereas Sirt2 activators may be useful in the treatment of metabolic disorders involving insulin resistance, such as type 2 diabetes and obesity, inhibitors of Sirt1 and Sirt2 could be used in cancers with up-regulated PI3K-AKT pathway activation.…”

“…There is substantial cross-talk between the insulin-PI3K-AKT-metabolic pathways and sirtuins (17,(31)(32)(33). For example, Sirt1 and Sirt2 can deacetylate and regulate the function of FoxO transcription factors, which are direct AKT targets (24,26,27,34).…”

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…Conversely, SIRT7 negatively regulates the transcription of genes outside of the rDNA repeats via histone H3K18 deacetylation (Barber et al , 2012). Recent evidence indicates that SIRT7 may have the capacity to act as an oncogene as its expression is elevated in several human cancers (Roth & Chen, 2014). The oncogenic potential of SIRT7 has been attributed to the transcriptional regulation of a specific set of genes through direct interaction with the EKL4 transcription factor.…”

Sirtuins, aging, and cardiovascular risks

“…Sirtuins are intimately linked to the cellular response to oxidative stress (Merksamer et al 2013); they might be activated during redox stress and may modulate crucial responses, including the adaptation to hypoxia and ameliorating ROS-induced pathologies (Webster et al 2012). Sirtuins also have been studied intensively as potential anti-aging and agerelated diseases targets (Baur et al 2012;Frye 2000;Haigis and Sinclair 2010;Hall et al 2013;Morris 2013;Roth and Chen 2014). It will be important to develop experimental models in which the levels of oxidative stress and the activities of sirtuins can be precisely modulated to determine how sirtuins have a causative role in lifespan extension.…”