ArticleCell death and differentiation2016
Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy.
Article in Cell death and differentiation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Histone demethylase KDM4A promotes endometrial cancer progression through an ERRγ-associated cell-cycle regulatory axis.International journal of biological sciences · 2026Article
- Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention.Molecular cancer · 2025Review
- KDM4A-driven SMAD5/TGFβ axis activation as a therapeutic target in cholangiocarcinoma: mechanistic insights and translational implications.Cell & bioscience · 2025Article
- Targeting N-Methyl-lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery.ChemMedChem · 2025Review
- HPV11 targeting KDM4A regulates the polarization of macrophage MCell communication and signaling : CCS · 2024Article
- The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism.Redox biology · 2024Article
- The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities.Genes & diseases · 2024Review
- Advances in the Application of Apoptotic Proteins and Alternative Splicing in Tumor Therapy: A Narrative Review.Iranian journal of public health · 2023Review
- Targeting epigenetic regulators to overcome drug resistance in cancers.Signal transduction and targeted therapy · 2023Review
- Engineering human JMJD2A tudor domains for an improved understanding of histone peptide recognition.Proteins · 2023Article
- Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis.Discover oncology · 2022Review
- Long non-coding RNA KIKAT/LINC01061 as a novel epigenetic regulator that relocates KDM4A on chromatin and modulates viral reactivation.PLoS pathogens · 2021Article
- Mechanistic insights into KDM4A driven genomic instability.Biochemical Society transactions · 2021Review
- KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches.Frontiers in oncology · 2021Review
- ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.Neoplasia (New York, N.Y.) · 2020Review
- Targeting castration-resistant prostate cancer with a novel RORActa pharmaceutica Sinica. B · 2020Article
- Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.Frontiers in cell and developmental biology · 2020Article
- Review
- KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis.Cell death & disease · 2019Article
- The Emerging Role of H3K9me3 as a Potential Therapeutic Target in Acute Myeloid Leukemia.Frontiers in oncology · 2019Review
Corrections and comments
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Authors and funding
12 authors.
Funding
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.
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