外照射放射治疗 (RT) 是前列腺癌 (PCa) 的领先一线治疗方法，近年来取得了重大进展。然而，在最坏的情况下，RT 耐药可能会出现并导致长期复发或疾病进展。因此，发现 PCa 放射增敏的新靶点至关重要。在此，我们生成了抗辐射 PCa 细胞系，并发现 p53 在抗辐射 PCa 细胞以及接受 RT 的复发/疾病进展 PCa 患者中高表达。机制剖析表明 RT 可以通过表观遗传调节促进 p53 表达。具体而言，在抗辐射 PCa 细胞中观察到，由于 KDM6B 活性增加，TP53 基因启动子处的 H3K27me3 占据量减少。此外，p53 对于有效的 DNA 损伤信号传导反应和长时间分次照射诱导应激后的细胞恢复至关重要。值得注意的是，GSK-J4 抑制 KDM6B 显着降低 p53 表达，从而减弱 PCa 细胞的放射抗性表型并阻碍体内 3D 肿瘤形成。总体而言，这项工作有助于提高对 p53 作为 DNA 损伤修复中信号转导介质的理解，以及表观遗传靶向对 PCa 放射增敏的影响。© 2023。四川大学华西医院。

External beam radiotherapy (RT) is a leading first-line therapy for prostate cancer (PCa), and, in recent years, significant advances have been accomplished. However, RT resistance can arise and result in long-term recurrence or disease progression in the worst-case scenario. Thus, making crucial the discovery of new targets for PCa radiosensitization. Herein, we generated a radioresistant PCa cell line, and found p53 to be highly expressed in radioresistant PCa cells, as well as in PCa patients with recurrent/disease progression submitted to RT. Mechanism dissection revealed that RT could promote p53 expression via epigenetic modulation. Specifically, a decrease of H3K27me3 occupancy at TP53 gene promoter, due to increased KDM6B activity, was observed in radioresistant PCa cells. Furthermore, p53 is essential for efficient DNA damage signaling response and cell recovery upon stress induction by prolonged fractionated irradiation. Remarkably, KDM6B inhibition by GSK-J4 significantly decreased p53 expression, consequently attenuating the radioresistant phenotype of PCa cells and hampering in vivo 3D tumor formation. Overall, this work contributes to improve the understanding of p53 as a mediator of signaling transduction in DNA damage repair, as well as the impact of epigenetic targeting for PCa radiosensitization.© 2023. West China Hospital, Sichuan University.