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

  • Cell Death Differ. 2016 Nov 1;23(11):1886-1896. doi: 10.1038/cdd.2016.92.
Junjian Wang  1 ,  Haibin Wang  2 ,  Ling-Yu Wang  1 ,  Demin Cai  1 ,  Zhijian Duan  1 ,  Yanhong Zhang  3 ,  Peng Chen  2 ,  June X Zou  1 ,  Jianzhen Xu  4 ,  Xinbin Chen  3 ,  Hsing-Jien Kung  1  5 ,  Hong-Wu Chen  1  6
Affiliations
  • 1. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA.
  • 2. First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3. Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA, USA.
  • 4. Shantou University Medical College, No. 22 Xinling Road, Shantou, China.
  • 5. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan.
  • 6. Veterans Affairs Northern California Health Care System, Mather, CA, USA.
PMID: 27612013 DOI: 10.1038/cdd.2016.92
Abstract

Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant Cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics.

Products