Loss of SIRT1 histone deacetylase expression associates with tumour progression in colorectal adenocarcinoma
- Correspondence to Professor Ki-Seok Jang, Department of Pathology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu 133-791, Seoul, Republic of Korea;
Contributors SJ contributed to acquisition and analysis of clinicopathological data, statistical analyses, and manuscript preparation. SJ and KM contributed to evaluation of immunohistochemical staining results. SP and KJ contributed to study design and data interpretation, and supervised the study.
- Accepted 24 March 2012
- Published Online First 3 May 2012
Background The class III histone deacetylase SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, and has been reported to serve diverse roles in various biological processes, such as caloric restriction, apoptosis, neuronal protection, cell growth, differentiation and tumourigenesis. With respect to tumourigenesis, there have been conflicting data supporting whether SIRT1 act as a tumour promoter or as a tumour suppressor.
Methods SIRT1 protein expression, determined by immunohistochemistry, was investigated in human normal colonic mucosa, adenoma, adenocarcinoma and metastatic tissue samples.
Results All normal colonic mucosa showed SIRT1 expression with no exception, and 42 (80.8%) of 52 adenomatous polyps were positive for SIRT1. However, only 208 (41.9%) of 497 colorectal adenocarcinomas were positive. Moreover, 45 (35.7%) of 126 metastatic tissues were positive. Collectively, the SIRT1 expression was gradually decreased during carcinogenesis and tumour progression. The associations between SIRT1 expression and clinicopathological parameters revealed that loss of SIRT1 expression was associated with proximal tumour location, mucinous histology and defective mismatch repair protein expression. This suggests that loss of SIRT1 expression is associated with the microsatellite instability phenotype of colorectal adenocarcinoma. In survival analyses, the loss of SIRT1 expression was significantly associated with overall survival (p=0.027, log-rank test) in univariable analysis, but multivariable analysis failed to achieve significance.
Conclusions SIRT1 expression was gradually decreased during the normal–adenoma–adenocarcinoma–metastasis sequence, suggesting a possible role of SIRT1 in tumour suppression in the colorectum, and a probable link to the microsatellite instability pathway.
- Colorectal cancer
- tumour suppressor
- microsatellite instability
- tumour biology
- colorectal cancer
Funding This work was supported by a grant from the research fund of Hanyang University (HY-2010-N) to KJ.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.