Expression of sirtuin 1 and 2 is associated with poor prognosis in non-small cell lung cancer patients.
BACKGROUND
Sirtuin 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.


METHODS
Protein 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.


RESULTS
High 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.


CONCLUSIONS
Our 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.
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Group for Translational Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
Ivana
I
Grbesa
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
María J
MJ
Pajares
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain.
Elena
E
Martínez-Terroba
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
Jackeline
J
Agorreta
Laboratory of Experimental Therapy, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
Ana-Matea
AM
Mikecin
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Marta
M
Larráyoz
Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Department of Pathology, University Hospital and Faculty of Medicine, University of Navarra, 31008 Pamplona, Spain.
Miguel A
MA
Idoate
Laboratory of Epigenomics, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
Koraljka
K
Gall-Troselj
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, 31008 Pamplona, Spain.
Ruben
R
Pio
Biomarkers Laboratory, Program of Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
Luis M
LM
Montuenga
D000083:Acetanilides / Q000494:pharmacology; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000083:Acetanilides; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C000594735:tenovin-1; D056564:Sirtuin 1; D056565:Sirtuin 2; D013890:Thiourea