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New tumor suppressor CXXC finger protein 4 inactivates mitogen activated protein kinase signaling

Haiqi Lu1, Wei Jin1, Jie Sun2

  • 1Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

FEBS Letters
|July 28, 2014
PubMed

Insights

Enhancer of Zeste Homolog 2 (EZH2) activates MAPK signaling by reducing CXXC4 expression. CXXC4 inhibits MAPK by blocking ERK1/2 interaction with MEK1/2, with L183 being crucial for this effect and cancer cell growth inhibition.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Enhancer of Zeste Homolog 2 (EZH2) is a key epigenetic regulator implicated in various malignancies.
  • Previous research established EZH2's role in promoting Wnt/β-catenin activation via CXXC4 downregulation.

Purpose of the Study:

  • To elucidate the mechanism by which CXXC4 influences MAPK signaling.
  • To investigate the role of the L183 residue in CXXC4's interaction with ERK1/2 and its functional consequences.

Main Methods:

  • Demonstration of CXXC4's inhibitory effect on MAPK signaling.
  • Analysis of CXXC4 binding to ERK1/2 and its impact on ERK1/2-MEK1/2 interaction.
  • Identification of the critical L183 residue in the CXXC4 ERK D domain.

Main Results:

  • CXXC4 directly inhibits MAPK signaling by binding to ERK1/2 and preventing its interaction with MEK1/2.
  • The L183 residue is essential for CXXC4-ERK1/2 binding and CXXC4's growth-inhibitory activity in human cancer cells.
  • EZH2 promotes MAPK signaling activation by suppressing CXXC4 expression.

Conclusions:

  • CXXC4 acts as a direct inhibitor of MAPK signaling through a mechanism involving the disruption of MEK1/2-ERK1/2 interaction.
  • The L183 site on CXXC4 is indispensable for its interaction with ERK1/2 and its anti-cancer growth effects.
  • EZH2 contributes to oncogenesis by upregulating MAPK signaling through the downregulation of CXXC4.
Keywords:
CXXC finger protein 4 (CXXC4)Enhancer of zeste homologue 2 (EZH2)Extracellular signal-regulated kinase (ERK)Gastric carcinogenesisMAP kinase (MEK)Mitogen-activated protein kinase (MAPK)

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