Abstract：
Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What\'s more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.
摘要：
顺铂耐药是针对晚期膀胱癌（BC）的全身治疗的主要挑战。关于顺铂耐药性调节的信息很少，其潜在机制需要阐明。这里,我们检测到肿瘤抑制因子的下调，PPP2R2B（丝氨酸/苏氨酸蛋白磷酸酶2A调节亚基），在BC中促进细胞增殖和迁移。更重要的是，PPP2R2B低表达与顺铂耐药相关。体外和体内实验证实PPP2R2B可以促进BC对顺铂的敏感性。在机制方面,我们确定了PPP2R2B作为核质转运分子的新功能。PPP2R2B通过介导IPO5与ISG15的结合促进ISG15进入细胞核。ISG15的核易位抑制DNA修复,通过激活STING途径进一步增加ISG15表达。此外,PPP2R2B被SUV39H1介导的组蛋白3赖氨酸9三甲基化下调，可以通过SUV39H1特异性抑制剂恢复，Chaetocin.我们的数据表明，PPP2R2B表达水平是化疗反应的潜在生物标志物，化疗联合chaetocin可能是BC患者可行的治疗策略。
