SIRT1 Histone Deacetylase Expression Is Associated with Microsatellite Instability and CpG Island Methylator Phenotype in Colorectal Cancer

The class III histone deacetylase SIRT1 plays an important role 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 play a role 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. Utilizing 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, related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in 8 CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1) and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (≥6/8 methylated CIMP-specific promoters, p=0.002) and MSI-high, (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, LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting a role of SIRT1 in gene silencing in this unique tumor subtype.