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.

中文翻译：

---

JARID1 靶向组蛋白 H3 去甲基化酶抑制剂表现出抗增殖活性并克服犬口腔黑色素瘤细胞系中的顺铂耐药性

组蛋白去甲基化酶在许多人类癌症中过度表达或表现出改变的活性，导致细胞周期动力学、DNA 修复动力学和治疗耐药性的改变。因此，组蛋白去甲基化酶的治疗靶向已成为人类肿瘤学中一个活跃且有前景的研究领域。然而，组蛋白去甲基化酶的作用和去甲基化酶抑制在犬癌中的潜在功效仍然很大程度上未知。在目前的工作中，我们通过探索组蛋白去甲基化酶抑制剂 (HDI) 在犬口腔黑色素瘤中的治疗潜力来解决这一知识空白。使用犬黑色素瘤细胞系，我们确定广谱 HDIs 会导致细胞存活率降低和 DNA 损伤修复动力学延长。然后我们展示了 JARID1B，一种与人类癌症的增殖-休眠调节和药物敏感性有关的组蛋白 H3 去甲基化酶，在犬肿瘤组织中高度表达。针对 JARID1B 和相关 JARID1 家族成员的 HDIs 显着降低了犬黑色素瘤细胞系的存活率，但似乎没有像广谱 HDI 治疗那样调节 DNA 损伤修复动力学。重要的是，我们发现 JARID1 靶向 HDIs 的抗增殖作用保留在对铂类化学疗法耐药的细胞系中，这表明当面对尽管使用常规疗法但仍会进展的口腔黑色素瘤时，HDI 可能作为一种可行的治疗策略. 显着降低了犬黑色素瘤细胞系的存活率，但似乎没有像广谱 HDI 治疗那样调节 DNA 损伤修复动力学。重要的是，我们发现 JARID1 靶向 HDIs 的抗增殖作用保留在对铂类化学疗法耐药的细胞系中，这表明当面对尽管使用常规疗法但仍会进展的口腔黑色素瘤时，HDI 可能作为一种可行的治疗策略. 显着降低了犬黑色素瘤细胞系的存活率，但似乎没有像广谱 HDI 治疗那样调节 DNA 损伤修复动力学。重要的是，我们发现 JARID1 靶向 HDIs 的抗增殖作用保留在对铂类化学疗法耐药的细胞系中，这表明当面对尽管使用常规疗法但仍会进展的口腔黑色素瘤时，HDI 可能作为一种可行的治疗策略.