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The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth.

Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA - PLoS ONE (2008)

Bottom Line: 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.Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed.

View Article: PubMed Central - PubMed

Affiliation: Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.

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 beta-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 beta-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 beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-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 beta-catenin-driven malignancies.

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Related in: MedlinePlus

SIRT1 expression occurs in a subset of human colon cancers and inversely correlates with the nuclear localization of β-catenin.(A) Representative images illustrating SIRT1 and β-catenin subcellular expression in human colon tumors. For each colon cancer case shown a text box insert indicates the detected protein (Image magnification 200×). (B) Correlation of SIRT1 and β-catenin expression in human colon tumors. The bar graph depicts cumulative immunostaining data from a tissue microarray of 81 colon cancer cases. Nuclear expression was scored as either no expression, weak expression, or moderate/strong expression. Positivity in nucleus was defined as moderate/strong expression. All slides were interpreted by two board certified pathologist blinded from any other clinical and laboratory data.
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pone-0002020-g005: SIRT1 expression occurs in a subset of human colon cancers and inversely correlates with the nuclear localization of β-catenin.(A) Representative images illustrating SIRT1 and β-catenin subcellular expression in human colon tumors. For each colon cancer case shown a text box insert indicates the detected protein (Image magnification 200×). (B) Correlation of SIRT1 and β-catenin expression in human colon tumors. The bar graph depicts cumulative immunostaining data from a tissue microarray of 81 colon cancer cases. Nuclear expression was scored as either no expression, weak expression, or moderate/strong expression. Positivity in nucleus was defined as moderate/strong expression. All slides were interpreted by two board certified pathologist blinded from any other clinical and laboratory data.

Mentions: To analyze the clinical relevance of our findings, we analyzed SIRT1 and β-catenin subcellular expression in a tissue microarray containing 81 human colon cancer samples. We found that a subset of colon cancers express SIRT1 in the nucleus (47/81 cases; 58%). When β-catenin expression was scored in these same colon cancers, a highly significant inverse correlation between the level of SIRT1 expression and nuclear β-catenin localization became apparent (p≤0.003, odds ratio 0.24 with 95% confidence interval 0.093–0.63) (Fig. 5A, B). Collectively, these observations suggest that modulation of β-catenin subcellular localization is an important component of the anti-tumorigenic effects of SIRT1 with potential diagnostic and therapeutic clinical relevance.


The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth.

Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA - PLoS ONE (2008)

SIRT1 expression occurs in a subset of human colon cancers and inversely correlates with the nuclear localization of β-catenin.(A) Representative images illustrating SIRT1 and β-catenin subcellular expression in human colon tumors. For each colon cancer case shown a text box insert indicates the detected protein (Image magnification 200×). (B) Correlation of SIRT1 and β-catenin expression in human colon tumors. The bar graph depicts cumulative immunostaining data from a tissue microarray of 81 colon cancer cases. Nuclear expression was scored as either no expression, weak expression, or moderate/strong expression. Positivity in nucleus was defined as moderate/strong expression. All slides were interpreted by two board certified pathologist blinded from any other clinical and laboratory data.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289879&req=5

pone-0002020-g005: SIRT1 expression occurs in a subset of human colon cancers and inversely correlates with the nuclear localization of β-catenin.(A) Representative images illustrating SIRT1 and β-catenin subcellular expression in human colon tumors. For each colon cancer case shown a text box insert indicates the detected protein (Image magnification 200×). (B) Correlation of SIRT1 and β-catenin expression in human colon tumors. The bar graph depicts cumulative immunostaining data from a tissue microarray of 81 colon cancer cases. Nuclear expression was scored as either no expression, weak expression, or moderate/strong expression. Positivity in nucleus was defined as moderate/strong expression. All slides were interpreted by two board certified pathologist blinded from any other clinical and laboratory data.
Mentions: To analyze the clinical relevance of our findings, we analyzed SIRT1 and β-catenin subcellular expression in a tissue microarray containing 81 human colon cancer samples. We found that a subset of colon cancers express SIRT1 in the nucleus (47/81 cases; 58%). When β-catenin expression was scored in these same colon cancers, a highly significant inverse correlation between the level of SIRT1 expression and nuclear β-catenin localization became apparent (p≤0.003, odds ratio 0.24 with 95% confidence interval 0.093–0.63) (Fig. 5A, B). Collectively, these observations suggest that modulation of β-catenin subcellular localization is an important component of the anti-tumorigenic effects of SIRT1 with potential diagnostic and therapeutic clinical relevance.

Bottom Line: 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.Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed.

View Article: PubMed Central - PubMed

Affiliation: Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.

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 beta-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 beta-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 beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-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 beta-catenin-driven malignancies.

Show MeSH
Related in: MedlinePlus