Abstract
BackgroundSirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology.Material and MethodsProtein levels of SIRT1 and SIRT2 were determined in non-small cell lung cancer (NSCLC) cell lines and primary tumors from 105 patients. Changes in proliferation were assessed after SIRT1 and SIRT2 downregulation in lung cancer cell lines using siRNA-mediated technology or tenovin-1, a SIRT1 and SIRT2 inhibitor.ResultsHigh SIRT1 and SIRT2 protein levels were found in NSCLC cell lines compared with non-tumor lung epithelial cells. The expression of SIRT1 and SIRT2 proteins was also significantly higher in lung primary tumors than in normal tissue (P<0.001 for both sirtuins). Stronger nuclear SIRT1 staining was observed in adenocarcinomas than in squamous cell carcinomas (P=0.033). Interestingly, in NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively). Moreover, the combination of high SIRT1 and SIRT2 expression was an independent prognostic factor for shorter recurrence-free survival (P=0.002) and overall survival (P=0.022). In vitro studies showed that SIRT1 and/or SIRT2 downregulation significantly decreased proliferation of NSCLC.ConclusionsOur results support the hypothesis that SIRT1 and SIRT2 have a protumorigenic role in lung cancer, promoting cell proliferation. Moreover, the expression of these proteins is associated with poor prognosis in NSCLC patients and may help to identify those NSCLC patients with high risk of recurrence that could benefit from adjuvant therapy after resection.
Highlights
Lung cancer is one of the most common cancers worldwide and is the most frequent cause of cancer-related mortality [1]
High Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) protein levels were found in non-small cell lung cancer (NSCLC) cell lines compared with nontumor lung epithelial cells
In NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively)
Summary
Lung cancer is one of the most common cancers worldwide and is the most frequent cause of cancer-related mortality [1]. Adjuvant chemotherapy after complete resection is recommended in non-small cell lung cancer (NSCLC) stage II-IIIA patients to reduce the risk of recurrence and improve overall survival. The best known members of this family are sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2), two NAD-dependent deacetylases that are involved in many cellular processes including cell proliferation, cell death, senescence and stress response. In cancer, both sirtuins might play a promoting or suppressing role, depending on the organ or even the species [2]. In this study we evaluated the relevance of these deacetylases in lung cancer biology
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