SIRT6 induces EMT and promotes cancer cell invasion and migration in prostate cancer

Abstract

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer related death in males in the developed countries. One of the major clinical challenges is the propensity for advanced PCa to metastasize to bone or other organs, which is primarily responsible for its effect on patient mortality. SIRT6, one of Sirtuins family members, is an important histone modifying protein that regulates diverse physiological functions such as aging and metabolism. Recently there is much evidence showing an involvement of SIRT6 in tumorigenesis. At present, relatively little is known about the role of SIRT6 in regulating prostate cancer or metastasis. In our study, we have used both prostate tumor tissues and prostate cancer cell lines to study the roles of SIRT6 in the development and progression of PCa. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal prostate tissues. Tissue microarray studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Depletion of SIRT6 by siRNA inhibited PCa cell proliferation. Bioinformatics analysis of the databases revealed that the high SIRT6 expression was associated with markedly shorter window of clinical recurrence, and the expression level of SIRT6 was significantly higher in PCa tissue with Gleason grade greater than seven. Further analysis indicated that SIRT6 expression increased along with the metastasis of PCa. We used PC-3 and DU145 cells to study whether SIRT6 could play a role in the migration and invasion of PCa cells. Indeed, SIRT6-deficiency markedly reduced cell migration and invasion. Compared with control siRNA treated cells, the protein level of N-cadherin reduced while E-cadherin level showed an increase after SIRT6 knockdown. We further revealed that SIRT6 regulated EMT-inducing transcription factor expression in PCa cells. Taken together, our findings indicate that SIRT6 is up-regulated in PCa, and the high expression of SIRT6 plays an important role in the progression of PCa as it facilitates cancer cell migration and invasion, and possibly metastasis. These data also suggest the therapeutic value of targeting SIRT6 in the treatment of metastatic PCa. ©2014 American Association for Cancer Research.