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

PLoS One. 2015 Apr 27;10(4):e0124670. doi: 10.1371/journal.pone.0124670. eCollection 2015.

Abstract

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.

Material and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology
  • Aged
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Gene Expression*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism
  • Sirtuin 2 / antagonists & inhibitors
  • Sirtuin 2 / genetics*
  • Sirtuin 2 / metabolism
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Acetanilides
  • Antineoplastic Agents
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • tenovin-1
  • Sirtuin 1
  • Sirtuin 2
  • Thiourea

Grants and funding

This work was supported by CIMA, the Spanish Ministries of Health/Economy and Competitivity and *Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional(FEDER)* (ISCIII: RTICC RD12/0036/0040, FIS-PI 10/00166 PI 11/00618,PI13/00806 and PI14/01686), and AECC Scientific Foundation (GCB14-2170) and a Seventh Framework Programme project (CURELUNG HEALTH-F2-2010-258677). IG was financed by Croatian Science Foundation (Brain Gain-Postdoc program, O-190-2011) and Croatian Ministry of Science, Education and Sport (098-0982464-2511). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.