015) association to a shorter time to recurrence (703 days versus 1,520 days) could be demonstrated for tumors with disrupted SIRT6 signaling (Fig. 5C and Supporting Table 2). Notably, when we compared the expression of the SIRT6 signature in the human HCCs around 182 genes (around 15%) significantly differed between both subclasses. These genes again were significantly associated with the prognosis

of patients overall, indicating that the these tumors retain a core SIRT6 signature (P < 0.001; data not shown). Furthermore, to evaluate Midostaurin molecular weight the clinical significance of the SIRT6 KO signature in molecular classification of HCC, we then compared the distribution of several clinical and pathological variables of the two subclasses using an univariate analysis (Table 2). The two subtypes of HCC were comparable with respect to sex, presence of cirrhosis in surrounding tissues, tumor size and stage, and vascular invasion. In contrast, a significant association with patient age, overall survival and recurrence, and Edmondson grade could be found. Furthermore, the two subclasses differed with respect to plasma AFP levels, which confirms the results of our

microarray analyses. Interestingly, while distribution of HCV-positive and HCV-negative patients was similar among the two subgroups, a significantly higher proportion of HBV-positive patients was found in the poor prognosis cluster. Notably, the significant association with overall survival remained present using multivariate analyses (P = 0.0157; hazard ratio, 1.9273; 95% Tamoxifen molecular weight confidence interval, 1.1351-3.2724). Moreover,

both gene set enrichment analysis and Oncomine meta-analysis suggested that the SIRT6 signature was significantly associated with cancer development, progression, and clinico-pathological medchemexpress features in several different tumor entities other than liver cancer, suggesting prognostic relevance of the SIRT6 signature for cancers other than HCC (Supporting Table 3 and Supporting Fig. 3). Thus, the SIRT6 signature is characterized by an unfavorable patient outcome with reduced survival and aggressive tumor phenotype in liver and other cancers. To support the idea that Sirt6 loss is creating a procancer environment in the liver, we investigated whether other changes played a role in tumorigenesis in Sirt6-deficient livers. SIRT6 plays a major role in the epigenetic regulation by modulating chromatin function.[24] Genetic loss of Sirt6 leads to genomic instability, metabolic defects, and degenerative pathologies with aging-associated degenerative phenotypes.[9, 25] Animals with Sirt6 deficiency die within 3 to 4 weeks of age. The observed phenotypic changes are predominantly caused by profound changes in the regulation of cellular metabolism. Consistent with this phenotype, Sirt6−/− animals show a significantly reduced level of blood glucose (P < 0.001) in comparison with control animals already at 3 weeks of age (Fig. 6A).