The class III
histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of
SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition,
SIRT1 may be involved in the well-known link between
obesity, cellular energy balance and
cancer. However, a comprehensive study of
SIRT1 using human
cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485
colorectal cancers in two independent prospective cohort studies, we detected
SIRT1 overexpression in 180 (37%)
tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight.
SIRT1 overexpression was associated with CIMP-high (> or =6 of 8 methylated CIMP-specific promoters, P=0.002) and
microsatellite instability (MSI)-high phenotype (P<0.0001). In both univariate and multivariate analyses,
SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P=0.008). In addition, mucinous component (P=0.01), high
tumor grade (P=0.02), and
fatty acid synthase overexpression (P=0.04) were significantly associated with
SIRT positivity in multivariate analysis.
SIRT1 was not significantly related with age, sex,
tumor location, stage, signet ring cells,
cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53,
beta-catenin, COX-2, or patient prognosis. In conclusion,
SIRT1 expression is associated with CIMP-high MSI-high
colon cancer, suggesting involvement of
SIRT1 in gene silencing in this unique
tumor subtype.