Unlike most other solid tumors, there is limited success of targeted agents in treating metastatic bladder cancer (BC), a lethal disease with a median overall survival of merely 13-15 months. No prevalent “drugable” driver mutations have been identified in muscle invasive bladder cancer (MIBC) so far. Several high profile publications in the past few years have put Sirt6, a member of the class III histone deacetylase in the center stage of cancer metabolism and DNA repair. We therefore assessed the expression and function of Sirt6 in MIBC. Inconsistent with its proposed function as a tumor suppressor in colon cancer, the gene expression datasets available in Oncomine did not reveal significant differences in Sirt6 mRNA levels among normal urothelium, superficial BC and MIBC. Compared to normal urothelium, carcinoma in situ, superficial BC, the median Sirt6 mRNA was the lowest in MIBC in the Dyrkjot bladder 3 dataset, but this was not statistically significant. We then studied Sirt6 protein expression with immunohistochemistry (IHC) in commercial tissue microarray as well as radical cystoprostatectomy samples in our total cancer care tumor bank. Sirt6 IHC were reviewed by pathologist and considered positive for Sirt6 if more than 5% of the tumor cells had at least 1+ Sirt6 nuclear staining. Positive Sirt6 IHC was detected in 33/56 (59%) of T2 (grade 1-3), 2/23 T3 (9%) and 0/3 T4 urothelial carcinoma. All the grade 3/high grade T3 urothelial carcinomas were negative for Sirt6 IHC. Negative Sirt6 IHC was also noted in 2 adenocarcinomas, 1 sarcomatoid carcinoma and 1 small cell MIBC. 1/18 (5%) lymph node metastasis had positive Sirt6 IHC. Consistent with its role of inhibiting aerobic glycolysis, bladder cancer cell lines with higher Srit6 have lower glucose uptake and lower lactate production. Knocking down Sirt6 expression in bladder cancer cell lines, however, did not sensitize bladder cancer lines to drug induced DNA damage. Among MIBC, much higher frequency of Sirt6 IHC positivity was noted in T2 urothelial carcinoma than T3, T4 and non-urothelial carcinomas. Data with bladder cancer cell lines suggest the function of Sirt6 in bladder cancer is primarily inhibiting aerobic glycolysis.

Citation Format: Minghui Wu, Shohreh Dickinson, Jingsong Zhang. Expression and function of Sirt6 in muscle invasive bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1590. doi:10.1158/1538-7445.AM2014-1590