Abstract
The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined. This study presents evidence that the ectopic expression of SIRT1 attenuates RAS- or MEK-driven ERK activation and reduces cellular proliferation and transformation in vitro. The attenuation of ERK activation by SIRT1 results from prompt dephosphorylation of ERK, while MEK activity remains unchanged. We identified that MKP1, a dual specific phosphatase for MAPK, was deacetylated by SIRT1. Deacetylation of MKP1 by direct interaction with SIRT1 increased the binding affinity to ERK which in turn facilitated inactivation of ERK. Taken together, these results suggest that SIRT1 would act as a tumor suppressor by modulating RAS-driven ERK activity through MKP1 deacetylation.
Highlights
Sirtuin 1 (SIRT1), a NAD+ -dependent class III histone deacetylase (HDAC), serves as an important deacetylase in diverse biological processes such as aging, stress response, metabolism, cell cycle, and so on [1,2,3]
We suggest that SIRT1 would protect from RAS-driven tumorigenesis through MAPK phosphatase 1 (MKP1) deacetylation
Considering the controversial role of SIRT1 in cancer, we evaluated the prognostic significance of SIRT1 by analyzing the correlation between SIRT1 expression and overall survival (OS) of cancer patients
Summary
Sirtuin 1 (SIRT1), a NAD+ -dependent class III histone deacetylase (HDAC), serves as an important deacetylase in diverse biological processes such as aging, stress response, metabolism, cell cycle, and so on [1,2,3]. SIRT1 plays a controversial role in carcinogenesis as either a suppressor or a driver [4,5]. Cumulative evidence shows that SIRT1 promotes tumorigenesis by inhibiting diverse tumor suppressors such as p53 [6,7] and forkhead class O transcription factors [8] through direct deacetylation. The relatively high expression of SIRT1 in diverse cancers [9,10] and its cancer-prone effects endorse the role of SIRT1 as a tumor driver [4,11]. 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]. The molecular mechanism of the tumor-suppressive role of SIRT1 in RAS-driven tumorigenesis has yet to be fully elucidated
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