In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer.

中文翻译：

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抑制 KDM4A 限制 SQLE 转录并诱导氧化应激失衡以抑制膀胱癌


在临床实践中，标准综合疗法对晚期膀胱癌的疗效有限，缺乏靶向治疗方案已得到充分认识。靶向肿瘤中的异常表观遗传修饰在癌症治疗中显示出相当大的潜力。通过在肿瘤类器官中进行药物筛选，我们发现 ML324 是一种组蛋白赖氨酸脱甲基酶 4A （KDM4A） 抑制剂，在体外和体内癌症模型中均表现出有效的抗肿瘤作用。从机制上讲，Kdm4a 使 H3K9me3 去甲基化，导致染色质打开并增加 Gabpa 对角鲨烯环氧化物酶 （Sqle） 基因启动子的可及性，从而导致转录激活。抑制 Kdm4a 下调 Sqle 转录，阻断胆固醇合成并导致角鲨烯 （SQA） 积累。该过程诱导活性氧 （ROS） 清除并抑制 JNK/c-Jun 磷酸化，最终诱导细胞凋亡。此外，ML324 治疗显着抑制膀胱癌患者来源的异种移植物 （PDX） 模型中的肿瘤生长。我们的研究结果揭示了调节氧化应激平衡的 Kdm4a-Sqle-ROS-JNK/c-Jun 信号轴的存在，为膀胱癌的靶向治疗提供了一种新的策略。