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Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway

Paula Colón-Bolea1, Piero Crespo

  • 1Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Cantabria, Santander, Spain.

Bioessays : News and Reviews in Molecular, Cellular and Developmental Biology
|November 11, 2014
PubMed

Insights

Lysine methylation, regulated by SMYD3, enhances Ras-driven cancers by affecting MAP3K2 and ERK1/2 signaling. Targeting SMYD3 shows promise in blocking tumor growth, especially with MEK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Lysine methylation is crucial in epigenetics and increasingly implicated in non-histone substrate regulation.
  • Deregulation of lysine methyltransferases and demethylases is observed in various human cancers.

Purpose of the Study:

  • To investigate the role of lysine methylation in cancer signaling pathways.
  • To explore the methyltransferase SMYD3 as a potential therapeutic target in Ras-driven cancers.

Main Methods:

  • Analysis of SMYD3 expression in tumors.
  • Investigating the methylation of MAP3K2 by SMYD3.
  • Assessing the impact of SMYD3 on Ras-ERK1/2 signaling and its interaction with PP2A.
  • Evaluating the synergistic effect of SMYD3 depletion with MEK inhibitors in preclinical cancer models.

Main Results:

  • SMYD3 is upregulated in multiple tumor types and enhances Ras-driven oncogenesis.
  • SMYD3 methylates MAP3K2, preventing its interaction with the phosphatase PP2A.
  • This methylation sustains Ras-ERK1/2 signaling, promoting lung and pancreatic adenocarcinoma formation.
  • SMYD3 depletion synergizes with MEK inhibitors to inhibit pancreatic tumor growth.

Conclusions:

  • Lysine methylation is a key regulator of tumor-promoting signaling pathways.
  • SMYD3 is a critical mediator in Ras-driven cancer development.
  • Targeting SMYD3 and its associated pathways represents a promising therapeutic strategy for cancer treatment.
Keywords:
ERKMAP3K2RasSMYD3cancerlysine methylationlysine methyltransferases

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