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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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Effect of SIRT1 overexpression on intestinal tumor formation and proliferation in Apcmin/+ mice.(A) Pictures of whole duodenal and ileal sections show gross intestinal tumors in mice overexpressing SIRT1 (SIRT1ΔSTOP) and controls (SIRT1STOP). Solid line indicates gastro-duodenal junction. Arrows indicate adenomas. White bar denotes 1 mm scale. (B) Average number of tumors according to intestinal location in SIRT1STOP control (n = 8) and SIRT1ΔSTOP experimental mice (n = 11). (C) Ki-67 staining of adenomas and proliferation rates. Pictures show Ki-67 immunohistochemical staining of adenomas from SIRT1STOP and SIRT1ΔSTOP. Proliferation index is expressed as the percent of Ki-67 stained adenoma cells (averaged for at least 10 adenomas per cohort). Mitotic rate is calculated as the number of histologically identifiable mitotic figures per 10 high-power fields (400×). Values in B and C are means±s.d.
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pone-0002020-g002: Effect of SIRT1 overexpression on intestinal tumor formation and proliferation in Apcmin/+ mice.(A) Pictures of whole duodenal and ileal sections show gross intestinal tumors in mice overexpressing SIRT1 (SIRT1ΔSTOP) and controls (SIRT1STOP). Solid line indicates gastro-duodenal junction. Arrows indicate adenomas. White bar denotes 1 mm scale. (B) Average number of tumors according to intestinal location in SIRT1STOP control (n = 8) and SIRT1ΔSTOP experimental mice (n = 11). (C) Ki-67 staining of adenomas and proliferation rates. Pictures show Ki-67 immunohistochemical staining of adenomas from SIRT1STOP and SIRT1ΔSTOP. Proliferation index is expressed as the percent of Ki-67 stained adenoma cells (averaged for at least 10 adenomas per cohort). Mitotic rate is calculated as the number of histologically identifiable mitotic figures per 10 high-power fields (400×). Values in B and C are means±s.d.

Mentions: APCmin/+, SIRT1STOP control mice that did not overexpress SIRT1 (referred to as SIRT1STOP) showed the typical signs of tumor morbidity at 16 weeks of age, as evidenced by overt anemia and cachexia, whereas APCmin/+ mice overexpressing SIRT1 (SIRT1ΔSTOP) displayed no overt signs of tumor associated morbidity (Fig. S1A, B). Examination of the gut lining at four months of age showed that the SIRT1ΔSTOP transgenic mice had significantly smaller and fewer tumors along the intestinal tract (Fig. 2A). Quantification of the tumor burden revealed a 3 to 4-fold reduction in the number and size of adenomas within the small intestine and colon of the SIRT1ΔSTOP mice (Fig. 2B). Ki-67 is a granular component of the nucleolus that is expressed exclusively in proliferating cells and is used as a prognostic marker in human neoplasias. Adenomas of the SIRT1ΔSTOP mice had a significant reduction in the numbers of mitoses (per high-power field) and Ki-67 staining, demonstrating that there was a decrease in adenoma proliferation (Fig. 2C). These data demonstrate that overexpression of SIRT1 in the gut at similar levels to those induced by CR is sufficient to mimic the tumor suppressive effect of CR in the APCmin/+ mouse.


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)

Effect of SIRT1 overexpression on intestinal tumor formation and proliferation in Apcmin/+ mice.(A) Pictures of whole duodenal and ileal sections show gross intestinal tumors in mice overexpressing SIRT1 (SIRT1ΔSTOP) and controls (SIRT1STOP). Solid line indicates gastro-duodenal junction. Arrows indicate adenomas. White bar denotes 1 mm scale. (B) Average number of tumors according to intestinal location in SIRT1STOP control (n = 8) and SIRT1ΔSTOP experimental mice (n = 11). (C) Ki-67 staining of adenomas and proliferation rates. Pictures show Ki-67 immunohistochemical staining of adenomas from SIRT1STOP and SIRT1ΔSTOP. Proliferation index is expressed as the percent of Ki-67 stained adenoma cells (averaged for at least 10 adenomas per cohort). Mitotic rate is calculated as the number of histologically identifiable mitotic figures per 10 high-power fields (400×). Values in B and C are means±s.d.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002020-g002: Effect of SIRT1 overexpression on intestinal tumor formation and proliferation in Apcmin/+ mice.(A) Pictures of whole duodenal and ileal sections show gross intestinal tumors in mice overexpressing SIRT1 (SIRT1ΔSTOP) and controls (SIRT1STOP). Solid line indicates gastro-duodenal junction. Arrows indicate adenomas. White bar denotes 1 mm scale. (B) Average number of tumors according to intestinal location in SIRT1STOP control (n = 8) and SIRT1ΔSTOP experimental mice (n = 11). (C) Ki-67 staining of adenomas and proliferation rates. Pictures show Ki-67 immunohistochemical staining of adenomas from SIRT1STOP and SIRT1ΔSTOP. Proliferation index is expressed as the percent of Ki-67 stained adenoma cells (averaged for at least 10 adenomas per cohort). Mitotic rate is calculated as the number of histologically identifiable mitotic figures per 10 high-power fields (400×). Values in B and C are means±s.d.
Mentions: APCmin/+, SIRT1STOP control mice that did not overexpress SIRT1 (referred to as SIRT1STOP) showed the typical signs of tumor morbidity at 16 weeks of age, as evidenced by overt anemia and cachexia, whereas APCmin/+ mice overexpressing SIRT1 (SIRT1ΔSTOP) displayed no overt signs of tumor associated morbidity (Fig. S1A, B). Examination of the gut lining at four months of age showed that the SIRT1ΔSTOP transgenic mice had significantly smaller and fewer tumors along the intestinal tract (Fig. 2A). Quantification of the tumor burden revealed a 3 to 4-fold reduction in the number and size of adenomas within the small intestine and colon of the SIRT1ΔSTOP mice (Fig. 2B). Ki-67 is a granular component of the nucleolus that is expressed exclusively in proliferating cells and is used as a prognostic marker in human neoplasias. Adenomas of the SIRT1ΔSTOP mice had a significant reduction in the numbers of mitoses (per high-power field) and Ki-67 staining, demonstrating that there was a decrease in adenoma proliferation (Fig. 2C). These data demonstrate that overexpression of SIRT1 in the gut at similar levels to those induced by CR is sufficient to mimic the tumor suppressive effect of CR in the APCmin/+ mouse.

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