The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth
Authors: Rafael de Cabo
William C Hahn
Philipp Oberdoerffer
Shuji Ogino
Ron Firestein
Anupama Bhimavarapu
Leonard P Guarente
Jennifer Campbell
Sandra Luikenhuis
Gil Blander
Shaday Michan
David A Sinclair
Charles Fuchs
Journal: PLoS ONE (2008)
Discipline: Multidisciplinary
Keywords: longevity genes; lifespan; mammals; cancer risk; Sir2/SIRT1 family
Affiliations: 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. 

Retracted: No

PubPeer comments:
 Figs 2C, 3C, 5C.  Transwell assay was performed to evaluate the invasiveness of Huh7 cells, 48 h transfected with siPokemon or nc siRNA ;  Transwell assay was performed to evaluate the invasiveness of HepG2 cell, 48 h transfected with pcDNA-GFP or pcDNA-Pokemon ;  Transwell assay was performed to evaluate the invasiveness of HepG2 cell, 48 h transfected with pcDNAGFP or pcDNA-Pokemon, and siMEF2D or nc siRNA. ![file] Figs 7D, 8D from [Zhang, Zhang Li (2015)] .  Transwell assays were employed to examine the invasiveness of A549 cells under the same conditions ;  Transwell assays were employed to examine the invasiveness of MRC-5 cells under the same conditions . ![file] Both teams of authors seem to be dipping into the same pool of Transwell images. , 
 Fig 2B.  western blot was used to confirm the above results ![file] *[left]* Figs 5B,C.  The expression level of HBP1 was detected by immunoblot analysis in U2OS and SaOS2 cells treated with miR-155 inhibitor ;  The expression level of HBP1 was detected by immunoblot analysis in hFOB1.19 and HEK293 cells transfected with miR-155 mimics . *[right]* Fig 7A from [Hong et al (2015)] .  A549 cells were infected with Ad-piR-55490 or and Ad-mTOR (10 MOI) as well as Ad-EGFP (10 MOI), and 48 h later, immunoblot analysis was performed to detect mTOR expression level . ![file] , 
 Fig 1B.  Western blot was also used to detect Pokemon protein level in invasive (n = 4) and non-invasive (n = 4) HCC specimens . ![file] Blue rectangle marks lanes that when flipped horizontally, are unexpectedly similar to *[left]* Fig 1C of [Wan et al (2016)]  Northern blotting was performed to confirm the expression profile of miR-155 ;  immunoblot assays were performed to detect the protein expression levels of HBP1 . ![file] *[right]* Fig 5A from [Liu et al (2015)] .  U2OS and a primary OS cell were infected with Ad-EGFP, OA-EGFP, Ad-IL-24 or OA-IL-24 (10 MOI) for 48 h. Immunoblot assays were performed to detect the expression level of IL-24 ;  U2OS and primary OS cells were infected with Ad-EGFP, OA-EGFP, Ad-IL-24 or OA-IL-24 (10 MOI) for 48 h. Immunoblot assays were performed to detect the expression level of Pgp, BCRP1 and MRP1 . ![file] Unexpected similarities. , 
 #2 *[left]* Fig 5B from [Wang, Zhao Zheng (2014)] .  Immunoblot analysis of WNT1 and phosphorylated and nuclear u03b2-catenin was performed in U-87 MG and U-251 MG cells transfected with Ad-miR-122 or Ad-EGFP (10 MOI) for 48 h. I have rearranged the WNT1 and beta-catenin bands (respectively flipping half-bands horizontally, and switching their order) for better comparison with ... *[right]* Figs 5B,C again. ![file] , 
 * **Pokemon is associated with the invasiveness of HCC in clinical specimen** * * Firstly, Pokemon expression was detected in HCC samples with or without intrahepatic invasion by quantitative PCR assay. The data indicated that the Pokemon expression level was significantly higher in HCC specimens with invasion, compared to non-invasive ones (non-invasive HCC: 0.732 u00b1 0.442; invasive HCC: 1.501 u00b1 0.414; nonHCC: 0.481 u00b1 0.375; p0.01; Fig. 1a). Furthermore, we employed transwell assays to compare the invasion ability of HCC cells derived from patients * * **Ethical standards** All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Huaiu2019an First Peopleu2019s Hospital, China) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Fresh HCC samples were collected from patients with their written informed consent at the Department of Hepatopancreatobiliary Surgery, Huaiu2019an First Peopleu2019s Hospital (Huaiu2019an, China). This study had been approved by the Ethical Review Board in the Review Board of Huaiu2019an First Peopleu2019s Hospital (No. 201403, Huaiu2019an, China). * There is no description of **any clinical patient group** in the Methods section. We only read of an animal study, and the use of two cell lines: * **Cell culture and HCC specimen** *  *Two human HCC cell lines, Huh7 and HepG2, were obtained from the ATCC (USA), and were cultured with DMEM containing 10 % FBS (GIBCO) at 37 C and 5 % CO2.* ,