Histone Demethylase KDM7A Regulates Androgen Receptor Activity, and Its Chemical Inhibitor TC-E 5002 Overcomes Cisplatin-Resistance in Bladder Cancer Cells.

Abstract

Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.

• Authors: Kyoung-Hwa Lee, Byung-Chan Kim, Seung-Hwan Jeong, Chang Wook Jeong, Ja Hyeon Ku, Hyeon Hoe Kim, Cheol Kwak
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 16 (Aug 06 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32781788 (Publication Type: Journal Article)

Chemical References

• RNA, Messenger
• Receptors, Androgen
• Jumonji Domain-Containing Histone Demethylases
• KDM7A protein, human
• Cisplatin

Topics

• Aged
• Aged, 80 and over
• Animals
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects, genetics)
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epigenesis, Genetic (drug effects)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Male
• Methylation
• Mice, Inbred NOD
• Middle Aged
• Neoplasm Invasiveness
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Tumor Burden (drug effects)
• Up-Regulation (drug effects, genetics)
• Urinary Bladder Neoplasms (drug therapy, genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays