The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

By R. Firestein, G. Blander, Shaday Michán, Philipp Oberdoerffer, S. Ogino, Jennifer H. Campbell, Anupama Bhimavarapu, Sandra Luikenhuis, R. de Cabo, C. Fuchs and 3 more. PLoS ONE, 2008

626 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/9783fa804df159b817f565c2820cea7f4c3f740d

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Citations in the corpus

Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “M SIRT1 deficiency promotes the development of multiple tumors by disrupting genomic stability, and SIRT1 overexpression inhibits the development of colon cancer by deacetylating b-catenin (Wang et al., 2008; Firestein et al., 2008).”
THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM (2012, neutral): “Interestingly, SIRT1 has also been involved in colorectal cancer by modulating the activity of b-catenin (Firestein et al., 2008), suggesting that sirtuins might have evolved to regulate different aspects of the tumorigenic process.”
Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice (2008, positive): “On the other hand, it was recently demonstrated that increased expression of SIRT1 reduces colon cancer formation in the APCmin/+ mouse model (Firestein et al., 2008).”
DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression (2008, positive): “Given that the effects of resveratrol may not be limited to SIRT1 activation, we generated a SIRT1 transgenic mouse strain (SIRT1STOP) that allows for Cre-mediated temporal and tissuespecific overexpression of SIRT1 via the deletion of a transcriptional STOP cassette (Firestein et al., 2008).”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “In the intestine, SIRT1 is known to suppress intestinal tumorigenesis and colon cancer growth (102).”
Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, positive): “regulating b-catenin signaling and glycolysis (Firestein et al., 2008; Sebastián et al., 2012).”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “Generation of a Whole Body SIRT1 Overexpressor Mouse A Cre-inducible SIRT1 transgenic mice harboring a transcriptional STOP element flanked with loxP sites inserted between a CAGGS promoter and the murine SIRT1 cDNA was described previously (Firestein et al., 2008).”
SIRT1 and other sirtuins in Metabolism (2013, background): “Significantly, several sirtuins have been reported to have tumor suppressing activities: SIRT1 overexpression is sufficient to suppress colon cancer growth in the APCmin/+ model [100].”