JARID1‐targeted histone H3 demethylase inhibitors exhibit anti‐proliferative activity and overcome cisplatin resistance in canine oral melanoma cell lines
| Autor: | Alexander E. Davies, Savannah J. Tobin, Hong Chang, Michael S. Kent |
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| Rok vydání: | 2021 |
| Předmět: |
Jumonji Domain-Containing Histone Demethylases
Pediatric Research Initiative 040301 veterinary sciences DNA damage Article H3K4 Cell Line Histones 0403 veterinary science 03 medical and health sciences Histone H3 Dogs 0302 clinical medicine Cell Line Tumor Genetics Canine Melanoma Animals 2.1 Biological and endogenous factors Dog Diseases Veterinary Sciences Aetiology Melanoma KDM5 Cancer Tumor drug resistance General Veterinary biology 04 agricultural and veterinary sciences DNA Repair Kinetics H3K9 Histone Drug Resistance Neoplasm 5.1 Pharmaceuticals 030220 oncology & carcinogenesis biology.protein Cancer research Neoplasm Demethylase Mouth Neoplasms Histone Demethylases Cisplatin Development of treatments and therapeutic interventions JARID1B |
| Zdroj: | Veterinary and comparative oncology, vol 19, iss 3 Vet Comp Oncol |
| ISSN: | 1476-5829 1476-5810 |
| Popis: | Histone demethylases are overexpressed or display altered activity in numerous human cancers leading to alterations in cell cycle dynamics, DNA repair kinetics, and therapeutic resistance. Consequently, therapeutic targeting of histone demethylases has become an active and promising area of research in human oncology. However, the role of histone demethylases and the potential efficacy of demethylase inhibition in canine cancers remains largely unknown. In the present work, we addressed this knowledge gap by exploring the therapeutic potential of histone demethylase inhibitors (HDIs) in canine oral melanoma. Using canine melanoma cell lines, we determined that broad spectrum HDIs result in decreased cell survival and prolonged DNA damage repair kinetics. We then showed that JARID1B, a histone H3 demethylase implicated in proliferation-dormancy regulation and drug sensitivity in human cancers, is highly expressed in canine tumour tissues. HDIs targeting JARID1B, and related JARID1 family members, significantly reduced survival fractions in canine melanoma cell lines, but did not appear to modulate DNA damage repair kinetics like broad spectrum HDI treatments. Importantly, we found that the anti-proliferative effects of JARID1-targeted HDIs are preserved in cell lines resistant to platinum-based chemotherapeutics, suggesting that HDIs may serve as a viable therapeutic strategy when faced with oral melanomas that progress despite the use of conventional therapies. |
| Databáze: | OpenAIRE |
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