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Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

Junjian Wang1, Haibin Wang2, Ling-Yu Wang1

  • 1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA.

Cell Death and Differentiation
|September 10, 2016
PubMed

Insights

KDM4A silences tumor cell expression of TRAIL and DR5. Inhibiting KDM4A with compound-4 (C-4) induces TRAIL and DR5, promoting cancer cell death and sensitizing tumors to TRAIL-based therapies.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Recombinant TRAIL and DR agonistic antibodies show limited anti-cancer efficacy.
  • Lack of death receptor (DR) expression in tumors is a key limitation.
  • KDM4A/JMJD2A, a chromatin regulator, silences tumor cell expression of TRAIL and its receptor DR5.

Purpose of the Study:

  • Investigate the role of KDM4A in regulating TRAIL and DR5 expression in cancer.
  • Determine if KDM4A inhibition can sensitize tumors to TRAIL-based therapeutics.
  • Elucidate the mechanism by which KDM4A regulates TRAIL and DR5.

Main Methods:

  • Utilized KDM4A small-molecule inhibitor compound-4 (C-4) and gene silencing.
  • Assessed TRAIL and DR5 expression in lung, breast, and prostate cancer cells.
  • Evaluated tumor growth inhibition and sensitization to TRAIL and ONC201.
  • Investigated epigenetic mechanisms involving histone modifying enzymes at the CHOP gene promoter.

Main Results:

  • KDM4A inhibition (C-4 or gene silencing) strongly induced TRAIL and DR5 expression in cancer cells.
  • This induction led to TRAIL-dependent apoptotic cell death and sensitized cells to TRAIL.
  • C-4 alone inhibited tumor growth, increasing TRAIL and DR5 expression and sensitizing tumors to ONC201.
  • Mechanistically, C-4 altered histone modifying complexes at the CHOP promoter, dissociating KDM4A/NCoR-HDAC and recruiting CBP.

Conclusions:

  • KDM4A is a critical epigenetic silencer of TRAIL and DR5 in tumors.
  • KDM4A inhibitors represent a novel strategy to sensitize tumors to TRAIL pathway-based therapies.
  • Targeting KDM4A enhances the efficacy of existing and novel TRAIL-inducing agents.

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