ERK dephosphorylation through MKP1 deacetylation by SIRT1 attenuates ras-driven tumorigenesis

Ok Seon Kwon, Haeseung Lee, Yun Jeong Kim, Hyuk Jin Cha, Na Young Song, Mi Ok Lee

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number909
JournalCancers
Volume12
Issue number4
DOIs
Publication statusPublished - 2020 Apr

Bibliographical note

Funding Information:
Funding: This research was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean Government (grant numbers NRF-2018R1C1B6008256 to M.-O.L.; NRF-2020R1C1C1003338 to N.-Y.S.; NRF-2019R1C1C1008710 to O.-S.K.), the Global Core Research Center (GCRC, #2011-0030001) and KRIBB Research Initiative Program.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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