Expression of SIRT1 and DBC1 in Gastric Adenocarcinoma

BACKGROUND: Sirtuin 1 (SIRT1) and deleted in breast cancer 1 (DBC1) are known as tumor suppressor or promoter genes. This may be due to their diverse functions and interaction with other proteins. Gastric adenocarcinoma is one of the most common malignancies, but little is known about its carcinogenesis. Therefore, we investigated the association of immunohistochemical expression of SIRT1, DBC1, p53, and beta-catenin and their variable clinicopathological characteristics. METHODS: We obtained samples from 452 patients who underwent gastrectomy. Tissue microarray blocks were constructed and immonohistochemical staining was performed. RESULTS: Expression of DBC1 and SIRT1 was associated with lower histologic grade, intestinal type of Lauren classification, and lower pT (p<0.001) and pN stage (DBC1, p=0.002; SIRT1, p<0.001). Association between absence of lymphatic invasion, and SIRT1 (p=0.001) and DBC1 (p=0.004) was observed. Cytoplasmic beta-catenin expression was associated with lower histologic grade, pT, pN, tumor-node-metastasis (TNM) stage, DBC1 (p<0.001), and SIRT1 (p=0.001). Expression of SIRT1 and DBC1 was not associated with p53 (p=0.063 and p=0.060). DBC1 was an independent good prognostic factor in multivariate analysis (p=0.012). CONCLUSIONS: SIRC1 and DBC1 can be considered to be good prognostic factors in gastric adenocarcinoma.

SIRT1 promotes DNA repair activity and deacetylation of Ku70

Human SIRT1 controls various physiological responses including cell fate, stress, and aging, through deacetylation of its specific substrate protein. In processing DNA damage signaling, SIRT1 attenuates a cellular apoptotic response by deacetylation of p53 tumor suppressor. The present study shows that, upon exposure to radiation, SIRT1 could enhance DNA repair capacity and deacetylation of repair protein Ku70. Ectopically over-expressed SIRT1 resulted in the increase of repair of DNA strand breakages produced by radiation. On the other hand, repression of endogenous SIRT1 expression by SIRT1 siRNA led to the decrease of this repair activity, indicating that SIRT1 can regulate DNA repair capacity of cells with DNA strand breaks. In addition, we found that SIRT1 physically complexed with repair protein Ku70, leading to subsequent deacetylation. The dominant-negative SIRT1, a catalytically inactive form, did not induce deacetylation of Ku70 protein as well as increase of DNA repair capacity. These observations suggest that SIRT1 modulates DNA repair activity, which could be regulated by the acetylation status of repair protein Ku70 following DNA damage.