The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Abstract

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β−catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β−catenin-driven malignancies.

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Although expression of SirT1 in intestines has been previously reported (Firestein et al, 2008), we found very low levels of SirT1 protein in intestines, despite the fact that the immunohistochemistry protocol was the same as the one we used for skin and that exposure time to the detection substrate was eight times longer ( Figure 7f). This low protein expression was confirmed by western blot (Figure 7g).…”

“…Firestein et al (2008) reported that Apc min / þ mice overexpressing SirT1 specifically in the gut villi had fewer and smaller polyps in their intestines, suggesting that SirT1 has tumor-suppressive effects. This seems inconsistent with our observation that Apc min / þ SirT1-null mice had similar numbers of polyps.…”

“…However, SirT1 is required for effective chemoprotection by resveratrol. This latter finding, along with the observation that overexpression of SirT1 inhibits polyp formation in the Apc min / þ mouse (Firestein et al, 2008), suggests that SirT1 might be a conditional tumor-suppressor whose antitumor activity is dependent on a threshold of enzymatic activity reached, either by gene overexpression or by drug exposure.…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…To assess the effect of SIRT1 on motor neurons, we examined several previously described mouse lines that can be engineered to overexpress or inactivate SIRT1 in motor neurons (Cohen, Supinski, Bonkowski, Donmez, & Guarente, 2009; Firestein et al, 2008; Rossi et al, 2011). Transgenic mice were created by breeding animals with a floxed‐stop cassette upstream of Sirt1 with mice expressing Cre recombinase under the choline acetyltransferase promoter.…”

Expression and role of SIRT1 in hepatocellular carcinoma

“…Despite frequent overexpression of sIrt1 in malignant ovarian serous tumors, increased expression of sIrt1 showed a correlation with increased overall survival (15). In addition, a recent study demonstrated suppressed intestinal tumor formation due to enhanced sIrt1 expression in a β-catenindependent mouse model of colon cancer, thereby indicating that the effects of sIrt1 may vary in different tumor models, depending on downstream targets of the enzyme (25). Further analysis of sIrt1 expression by cancer cells is required for determination of its mechanism of action and its importance in carcinogenesis.…”