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JMJD2A promotes cellular transformation by blocking cellular senescence through transcriptional repression of the

Frédérick A Mallette1, Stéphane Richard

  • 1Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Sir Mortimer B Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.

Cell Reports
|November 22, 2012
PubMed

Insights

Oncogenic Ras can cause cancer, but needs cooperating genes. Researchers found JMJD2A (KDM4A) promotes cell transformation by inhibiting the tumor suppressor p53 pathway, highlighting JMJD2A as a potential cancer therapy target.

Area of Science:

  • Cellular biology
  • Oncology
  • Molecular mechanisms of cancer

Background:

  • Cellular senescence is a key mechanism preventing tumor formation.
  • Ras oncogene activation is common in cancers but often requires cooperating factors for full transformation.
  • Identifying cooperating oncogenes is crucial for understanding cancer development.

Purpose of the Study:

  • To identify cooperating oncogenes that collaborate with Ras to drive cellular transformation.
  • To elucidate the molecular mechanisms by which these cooperating oncogenes promote tumorigenesis.
  • To investigate the role of JMJD2A/KDM4A in Ras-mediated cellular processes and cancer.

Main Methods:

  • Investigated the role of lysine demethylase JMJD2A/KDM4A as a cooperating oncogene with Ras.
  • Analyzed the regulation of the p53 pathway and its target CHD5 by JMJD2A.
  • Examined JMJD2A expression in mouse and human lung cancer samples.
  • Performed gene depletion experiments in human lung cancer cell lines.

Main Results:

  • JMJD2A/KDM4A was identified as a cooperating oncogene with Ras.
  • JMJD2A negatively regulates Ras-induced senescence and promotes cellular transformation.
  • JMJD2A inhibits the p53 pathway by targeting the tumor suppressor CHD5.
  • JMJD2A is overexpressed in lung cancers and its depletion induces senescence in cancer cells.

Conclusions:

  • JMJD2A/KDM4A acts as an oncogene by suppressing the p53 pathway, cooperating with oncogenic Ras.
  • JMJD2A is a critical regulator of senescence and cellular transformation.
  • JMJD2A represents a promising therapeutic target for Ras-driven cancers.

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