BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.
METHODS: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.
RESULTS: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.
CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.
- Aniline Compounds/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Knockdown Techniques
- Jumonji Domain-Containing Histone Demethylases/genetics
- Mesothelioma, Malignant/drug therapy
- Pyrazines/administration & dosage
- Pyrazoles/administration & dosage
- Pyrimidinones/administration & dosage
- Sulfonamides/administration & dosage
- Up-Regulation/drug effects
- Xenograft Model Antitumor Assays