Sirt1 protects from K‐Ras‐driven lung carcinogenesis. (18th July 2018)

• Record Type: Journal Article
• Authors: Costa‐Machado, Luis Filipe; Martín‐Hernández, Roberto; Sanchez‐Luengo, Miguel Ángel; Hess, Katharina; Vales‐Villamarin, Claudia; Barradas, Marta; Lynch, Cian; de la Nava, Daniel; Diaz‐Ruiz, Alberto; de Cabo, Rafael; Cañamero, Marta; Martinez, Lola; Sanchez‐Carbayo, Marta; Herranz, Daniel; Serrano, Manuel; Fernandez‐Marcos, Pablo J
• Is Part Of: EMBO reports. Volume 19:Number 9(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-18
• Subjects: K‐RAS -- non‐small cell lung carcinoma -- SIRT1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201643879
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The NAD + ‐dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non‐small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K‐RAS. Therefore, we investigated the effect of SIRT1 on K‐RAS‐driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K‐RAS in a MEK and PI3K‐dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K‐Ras G12V ‐driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1‐Tg pneumocytes, isolated shortly after K‐Ras G12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K‐RAS‐driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1–K‐RAS axis could be a therapeutic target for NSCLCs. Synopsis: The NAD + ‐dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. This study demonstrates a tumor suppressive role for SIRT1 in K‐RAS‐driven lung adenocarcinomas in mice and humans. Sirt1 protects against oncogenic K‐Ras‐driven lung adenocarcinoma in mice and humans. Sirt1 overexpression in mouse pneumocytes alters pathways involved in tumor development. Oncogenic K‐Ras activation reduces Sirt1 protein stability through the MAPK pathway. Abstract : The NAD + ‐dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. This study demonstrates a tumor suppressive role for SIRT1 in K‐RAS‐driven lung adenocarcinomas in mice and humans.