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Abstract：
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
摘要：
化疗耐药是鼻咽癌患者治疗失败的主要原因,但鼻咽癌化疗耐药的确切调控机制仍有待阐明。这里,我们确定PJA1是参与鼻咽癌化疗耐药的关键E3泛素连接酶,在对多西他赛-顺铂-5-氟尿嘧啶诱导化疗无反应的鼻咽癌患者中高表达.我们发现PJA1通过抑制GSDME介导的鼻咽癌细胞焦亡促进多西他赛耐药。机械上,PJA1通过在K88处增加其K48连接的泛素化来促进线粒体蛋白PGAM5的降解，这进一步促进了S637处的DRP1磷酸化并减少了线粒体活性氧的产生，导致GSDME介导的焦亡和抗肿瘤免疫反应的抑制。PGAM5敲低完全恢复了PJA1敲低的多西他赛增敏效应。此外，PJA1与小分子抑制剂RTA402的药理学靶向增强了鼻咽癌的多西他赛敏感性。临床上,PJA1高表达表明TPFIC在鼻咽癌患者中的生存率低且临床疗效差。我们的研究强调了E3连接酶在调节化学耐药性中的重要作用，并基于靶向泛素-蛋白酶体系统为鼻咽癌提供了治疗策略。
