SIRT2-deacetylase activity is a potential predictive and prognostic marker in lung cancer patients

Abstract Background: SIRT2 has been described as a tumor suppressor, whereas our previous study using an LSL-KRASG12D mouse model showed that Sirt2 loss induced lung tumorigenesis in vivo through increased KRAS acetylation (K147) and activity. However, there is limited information about the clinical significance of SIRT2 expression and/or activity in lung cancer patients. Purpose: The aim of this study was to investigate the associations between SIRT2 levels and activity with clinical-pathological characteristics and patient outcomes in lung cancer. Materials and Methods: SIRT2 expression and activity was analyzed using a tissue microarray of 162 resected lung cancer samples from Northwestern Memorial Hospital. To assess SIRT2 expression, we used an antibody against SIRT2 for immunohistochemistry. To assess SIRT2 activity, we evaluated acetylated levels of two specific deacetylation targets, α-tubulin (K40) and KRAS (K147). For all tested markers, staining intensity of each tissue sample was scored as 0 (no signal), + 1 (weak), + 2 (distinct), + 3 (strong). The percentage of each positive staining was categorized as A (<25%), B (25~50%), C (>50%). Following statistical analysis, it was determined whether SIRT2 expression and activity were associated with several clinical parameters or outcomes. p < 0.05 was assumed statistically significant. Results: Acetylated α-tubulin and acetylated KRAS in lung tumor samples were significantly correlated with each other (p<0.05), but not with SIRT2 expression. Of note, acetylated α-tubulin was significantly associated with TTF1 expression (p<0.05), staging (p<0.005), pleural metastasis (p<0.005), surgery (p<0.001), and chemotherapy (p<0.005). Acetylated KRAS had significant associations with surgery (p<0.005), lymph nodal status (p<0.05) and pleural metastasis (p<0.05). Kaplan-Meier analysis further indicated that both TTF1 and acetylated α-tubulin were independent predictors of patient survival (p=0.005 and p=0.028, respectively). Conclusions: Our data implicated that SIRT2 deacetylation activity, but not SIRT2 expression levels, could represent an optimal predictive and prognostic factor in lung cancer. Based on this finding, strategies to increase SIRT2 activity might be favorable in clinical treatment protocols for lung cancer. Citation Format: Yang Guo, Ha Yong Song, Kirtee Raparia, Athanassios Vassilopoulos. SIRT2-deacetylase activity is a potential predictive and prognostic marker in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4356.