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

Junjian Wang, Haibin Wang, Ling Yu Wang, Demin Cai, Zhijian Duan, Yanhong Zhang, Peng Chen, June X Zou, Jianzhen Xu, Xinbin Chen, Hsing-Jien Kung, Hongwu Chen

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.Cell Death and Differentiation advance online publication, 9 September 2016; doi:10.1038/cdd.2016.92.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Sep 9 2016

Fingerprint

Epigenomics
Neoplasms
Death Domain Receptors
Therapeutics
Cell Death
TNF-Related Apoptosis-Inducing Ligand Receptors
Histone Acetyltransferases
Co-Repressor Proteins
MAP Kinase Signaling System
Gene Silencing
Histones
Chromatin
Publications
Cell Differentiation
Lung Neoplasms
Prostatic Neoplasms
Breast
Clinical Trials
Antibodies
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. / Wang, Junjian; Wang, Haibin; Wang, Ling Yu; Cai, Demin; Duan, Zhijian; Zhang, Yanhong; Chen, Peng; Zou, June X; Xu, Jianzhen; Chen, Xinbin; Kung, Hsing-Jien; Chen, Hongwu.

In: Cell Death and Differentiation, 09.09.2016.

Research output: Contribution to journalArticle

Wang, Junjian ; Wang, Haibin ; Wang, Ling Yu ; Cai, Demin ; Duan, Zhijian ; Zhang, Yanhong ; Chen, Peng ; Zou, June X ; Xu, Jianzhen ; Chen, Xinbin ; Kung, Hsing-Jien ; Chen, Hongwu. / Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. In: Cell Death and Differentiation. 2016.
@article{b16ee3a544b741e1b0a70b3228f94e7c,
title = "Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy",
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.Cell Death and Differentiation advance online publication, 9 September 2016; doi:10.1038/cdd.2016.92.",
author = "Junjian Wang and Haibin Wang and Wang, {Ling Yu} and Demin Cai and Zhijian Duan and Yanhong Zhang and Peng Chen and Zou, {June X} and Jianzhen Xu and Xinbin Chen and Hsing-Jien Kung and Hongwu Chen",
year = "2016",
month = "9",
day = "9",
doi = "10.1038/cdd.2016.92",
language = "English (US)",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

AU - Wang, Junjian

AU - Wang, Haibin

AU - Wang, Ling Yu

AU - Cai, Demin

AU - Duan, Zhijian

AU - Zhang, Yanhong

AU - Chen, Peng

AU - Zou, June X

AU - Xu, Jianzhen

AU - Chen, Xinbin

AU - Kung, Hsing-Jien

AU - Chen, Hongwu

PY - 2016/9/9

Y1 - 2016/9/9

N2 - 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.Cell Death and Differentiation advance online publication, 9 September 2016; doi:10.1038/cdd.2016.92.

AB - 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.Cell Death and Differentiation advance online publication, 9 September 2016; doi:10.1038/cdd.2016.92.

UR - http://www.scopus.com/inward/record.url?scp=84986538313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84986538313&partnerID=8YFLogxK

U2 - 10.1038/cdd.2016.92

DO - 10.1038/cdd.2016.92

M3 - Article

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

ER -