Expression and function of SIRT6 in muscle invasive urothelial carcinoma of the bladder.

SIRT6, a member of the class III histone deacetylase, has been shown to inhibit glycolysis and promote DNA double strand break repairs. Despite of its proposed tumor suppressor role, no significant differences in SIRT6 mRNA levels among normal bladder urothelium, non-muscle invasive, and muscle invasive urothelial carcinoma were noted in the two largest bladder cancer gene expression datasets available in Oncomine. We therefore studied the expression and function of SIRT6 in muscle invasive urothelial carcinoma of the bladder. Immunohistochemistry studies of SIRT6 on radical cystectomy samples showed a dramatic decline of SIRT6 expression when bladder cancer progressed from T2 to T4. Functional study with bladder cancer cell lines confirmed its role in inhibiting glycolysis and cell proliferation. Reducing SIRT6 with siRNA, however, did not sensitize bladder cancer cells to drug induced DNA damage. The differential expression patterns of SIRT6 amongst different T stages of muscle invasive bladder cancers indicate less reliance on glycolysis when urothelial carcinoma invades deeper through the bladder and into the adjacent tissues.