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.