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

Ok-Seon Kwon1, Haeseung Lee2, Yun-Jeong Kim3,4

  • 1Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.

Cancers
|April 12, 2020
PubMed

Insights

Sirtuin 1 (SIRT1) acts as a tumor suppressor by deactivating the ERK pathway. It achieves this by deacetylating MKP1, enhancing ERK inactivation and reducing cancer cell growth in RAS-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The role of Sirtuin 1 (SIRT1) in cancer is complex, with evidence supporting both oncogenic and tumor-suppressive functions.
  • SIRT1's involvement in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been implicated in tumorigenesis.

Purpose of the Study:

  • To elucidate the molecular mechanism by which SIRT1 suppresses RAS-driven tumorigenesis.
  • To investigate SIRT1's effect on ERK pathway activation and cellular proliferation.

Main Methods:

  • Ectopic expression of SIRT1 in cell models.
  • Assessment of ERK and MEK pathway activation.
  • Analysis of cellular proliferation and transformation assays.
  • Investigation of the interaction between SIRT1, MKP1, and ERK.

Main Results:

  • Ectopic SIRT1 expression attenuated RAS- or MEK-driven ERK activation and reduced cellular proliferation and transformation.
  • SIRT1 directly deacetylated MKP1 (MAPK phosphatase 1), increasing its binding affinity to ERK and facilitating ERK inactivation.
  • MEK activity remained unaffected by SIRT1 expression.

Conclusions:

  • SIRT1 functions as a tumor suppressor in the context of RAS-driven cancers.
  • SIRT1 modulates RAS-driven ERK activity via deacetylation of MKP1, representing a potential therapeutic target.
Keywords:
ERKMKP1RASSIRT1deacetylationtumorigenesis

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