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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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SIRT1 inhibits β-catenin driven cell proliferation and transcriptional activity.(A–D) Stable LN-CAP, DLD1, HCT116 and RKO cell lines expressing the indicated product were seeded and cell number was monitored at different time points. Western blot were performed with SIRT1, actin or β-catenin antibodies. (E) DLD1 stable cell lines expressing Topflash-LuciferasePEST were infected with the indicated constructs. Cells were analyzed by western blot with antibodies against SIRT1 and β-catenin. Luciferase activity was normalized for total sample protein and represents three independent experiments done in quadruplicate.
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pone-0002020-g003: SIRT1 inhibits β-catenin driven cell proliferation and transcriptional activity.(A–D) Stable LN-CAP, DLD1, HCT116 and RKO cell lines expressing the indicated product were seeded and cell number was monitored at different time points. Western blot were performed with SIRT1, actin or β-catenin antibodies. (E) DLD1 stable cell lines expressing Topflash-LuciferasePEST were infected with the indicated constructs. Cells were analyzed by western blot with antibodies against SIRT1 and β-catenin. Luciferase activity was normalized for total sample protein and represents three independent experiments done in quadruplicate.

Mentions: To gain insights into the mechanisms by which SIRT1 reduces cellular proliferation, we examined the effect of SIRT1 on the growth rate of several well characterized cancer cell lines. The proliferation of LNCaP prostate cancer cells was greatly reduced by overexpression of SIRT1 and the effect was similar to suppressing β-catenin itself (Fig. 3A). This observation suggested that SIRT1 and β-catenin function in the same cellular context. To further explore this possibility, we overexpressed SIRT1 and a catalytically inactive SIRT1 mutant (SIRT1ΔHY) in different human colon cancer cell lines whose growth is driven by constitutively active β-catenin (HCT116 and DLD1). A human colon cancer cell line in which β-catenin is inactive (RKO) served as a negative control. Increased SIRT1 expression greatly reduced proliferation in both colon cancer cell lines with constitutively active β-catenin but not in the β-catenin-inactive cell line (Fig. 3A–D). The SIRT1ΔHY catalytic mutant had no significant effect on cellular proliferation in any of the cell lines (Fig. 3B–D). Thus, SIRT1 suppresses β-catenin-driven proliferation and its catalytic activity is apparently required for this effect.


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 inhibits β-catenin driven cell proliferation and transcriptional activity.(A–D) Stable LN-CAP, DLD1, HCT116 and RKO cell lines expressing the indicated product were seeded and cell number was monitored at different time points. Western blot were performed with SIRT1, actin or β-catenin antibodies. (E) DLD1 stable cell lines expressing Topflash-LuciferasePEST were infected with the indicated constructs. Cells were analyzed by western blot with antibodies against SIRT1 and β-catenin. Luciferase activity was normalized for total sample protein and represents three independent experiments done in quadruplicate.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002020-g003: SIRT1 inhibits β-catenin driven cell proliferation and transcriptional activity.(A–D) Stable LN-CAP, DLD1, HCT116 and RKO cell lines expressing the indicated product were seeded and cell number was monitored at different time points. Western blot were performed with SIRT1, actin or β-catenin antibodies. (E) DLD1 stable cell lines expressing Topflash-LuciferasePEST were infected with the indicated constructs. Cells were analyzed by western blot with antibodies against SIRT1 and β-catenin. Luciferase activity was normalized for total sample protein and represents three independent experiments done in quadruplicate.
Mentions: To gain insights into the mechanisms by which SIRT1 reduces cellular proliferation, we examined the effect of SIRT1 on the growth rate of several well characterized cancer cell lines. The proliferation of LNCaP prostate cancer cells was greatly reduced by overexpression of SIRT1 and the effect was similar to suppressing β-catenin itself (Fig. 3A). This observation suggested that SIRT1 and β-catenin function in the same cellular context. To further explore this possibility, we overexpressed SIRT1 and a catalytically inactive SIRT1 mutant (SIRT1ΔHY) in different human colon cancer cell lines whose growth is driven by constitutively active β-catenin (HCT116 and DLD1). A human colon cancer cell line in which β-catenin is inactive (RKO) served as a negative control. Increased SIRT1 expression greatly reduced proliferation in both colon cancer cell lines with constitutively active β-catenin but not in the β-catenin-inactive cell line (Fig. 3A–D). The SIRT1ΔHY catalytic mutant had no significant effect on cellular proliferation in any of the cell lines (Fig. 3B–D). Thus, SIRT1 suppresses β-catenin-driven proliferation and its catalytic activity is apparently required for this effect.

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