The highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression highlights the importance of targeting EZH2 in bladder cancer. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium, and the anti-oncogenic effects of retinoids are well established. Therefore, our aim is to simultaneously target EZH2 and retinoic acid signaling in bladder cancer to potentiate the therapeutic response. Here we report that this coordinated targeting strategy stimulates an anti-oncogenic profile, as reflected by inducing a synergistic reduction in cell viability that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. This study characterized anti-oncogenic transcriptional reprogramming centered on the transcriptional regulator CHOP by stimulating the endoplasmic reticulum stress response. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of a subset of genes involved in unfolded protein responses, reflecting the molecular mechanism underlying this co-targeting strategy. These findings highlight the importance of co-targeting the EZH2 and retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.

膀胱癌的高度突变性质，含有与 Polycomb 介导的抑制相反的染色质调节基因突变，凸显了靶向EZH2在膀胱癌中的重要性。此外，视黄酸信号通路在尿路上皮发育和稳态中的关键作用以及类视黄醇的抗癌作用已得到充分证实。因此，我们的目标是同时靶向膀胱癌中的EZH2和视黄酸信号传导以增强治疗反应。在这里，我们报告说，这种协调的靶向策略刺激了抗癌特征，这通过诱导细胞活力的协同降低来反映，这与以合作和精心策划的方式增加细胞凋亡和细胞周期停滞相关。本研究通过刺激内质网应激反应来表征以转录调节因子CHOP为中心的抗癌转录重编程。我们进一步描绘了一种分子机制，EZH2通过该机制维持 H3K27me3 介导的对参与未折叠蛋白反应的基因子集的抑制，反映了这种共靶向策略背后的分子机制。这些发现强调了联合靶向EZH2和视黄酸通路在膀胱癌中的重要性，并鼓励设计使用类维生素A与 EZH2 抑制剂联合治疗膀胱癌的新型治疗方法。