Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.

基于顺铂的化疗可改善鼻咽癌（NPC）患者远处转移的控制；然而，大约30%的患者由于获得性耐药而导致治疗失败。众所周知，表观遗传调控会导致顺铂耐药；然而，其根本机制仍然知之甚少。在这里，我们发现赖氨酸特异性去甲基酶 5B (KDM5B) 过度表达，并且与鼻咽癌患者的肿瘤进展和顺铂耐药相关。我们还表明，在体外和体内，KDM5B 的特异性抑制会损害 NPC 的进展并逆转顺铂耐药性。此外，我们发现KDM5B通过直接降低ZBTB16启动子处的H3K4me3来抑制ZBTB16的表达，随后增加拓扑异构酶II-α（TOP2A）的表达，从而赋予NPC顺铂耐药性。此外，我们还发现去泛素酶 USP7 对于去泛素化和稳定 KDM5B 至关重要。更重要的是，USP7 的缺失通过破坏 NPC 细胞中 KDM5B 的稳定性来增加对顺铂的敏感性。因此，我们的研究结果表明，USP7 通过 ZBTB16/TOP2A 轴稳定 KDM5B 并促进顺铂耐药，这表明靶向 KDM5B 可能是治疗 NPC 的一种有前途的顺铂增敏策略。