Sirt1 protects from K‐Ras‐driven lung carcinogenesis

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-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 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.

Avenanthramide C suppresses hypoxia-induced cyclooxygenase-2 expression through sirtuin1 activation in non-small-cell lung cancer cells

“…SIRT1 protects from K-Ras-driven lung carcinogenesis (Costa-Machado et al 2018). The abnormal expression of SIRT1 was involved in the development of non-small-cell lung cancer (Yang 2018).…”

ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis

“…Recently, SIRT1 has been demonstrated to suppress KRAS-driven lung carcinogenesis by inhibiting PI3K and MEK pathways [16]. According to the TCGA and Gene Expression Omnibus (GEO) databases, we also found that SIRT1 overexpression was correlated to better prognosis in human patients with cancers that frequently carry oncogenic RAS mutations (Figure 1 and Figure S1).…”

“…This association was also observed in independent cohorts of lung and breast cancer patients ( Figure 1B,C). Considering a previous report that increased SIRT1 expression protects from KRAS-driven lung carcinogenesis [16], we further investigated RAS-dependency in the correlation between SIRT1 expression and survival rates of patients with pancreatic, colorectal, and lung cancers, which frequently carry KRAS mutation(s), particularly on glycine 12 ( Figure 1D). There were no significant differences in the survival rates between SIRT1-high and -low groups ( Figure 1E and Figure S1B), or between KRAS mutant and wild-type groups ( Figure S1C).…”

“…In addition, Sirt1 +/− and p53 +/− mice develop more tumors in multiple tissues, suggesting that SIRT1 acts as a tumor suppressor [15]. Recently, it has been reported that SIRT1 suppresses Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung tumorigenesis by interfering in KRAS-induced transcriptional programs [16]. However, the molecular mechanism of the tumor-suppressive role of SIRT1 in RAS-driven tumorigenesis has yet to be fully elucidated.…”

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

“…Changes in SIRT1 expression levels are frequent molecular events in human cancers 11,[19][20][21] . Recent data have shown low expression levels of SIRT1 in human colon cancer, lung cancer, and glioblastoma.…”