DNA损伤修复是肿瘤细胞保护自身免于DNA损伤相关死亡的关键机制，但目前有关DNA损伤修复的调控仍不明确。组蛋白甲基化转移酶KMT2D是我们前期研究新发现的前列腺癌促癌基因，预实验显示，KMT2D缺失会导致前列腺癌细胞出现DNA损伤修复障碍，抑制泛素依赖的DNA修复关键基因HERC2的表达，增加PARP抑制剂奥拉帕尼对细胞的杀伤。因此，我们认为KMT2D可能通过激活HERC2转录促进DNA损伤的修复，进而增强肿瘤细胞对损伤因素的抵抗性；抑制KMT2D表达会增加肿瘤细胞对DNA损伤靶点药物的敏感性。本项目拟通过临床病例样本、KMT2D沉默和敲除细胞模型以及基因敲除小鼠模型，阐明KMT2D通过HERC2基因调控DNA损伤修复的机制，并利用类器官模型，评价KMT2D的临床应用价值，为前列腺癌的治疗提供新的药物靶点。

The DNA repair system is essential for tumor cells to protect cells form death caused by DNA damage. However, the underlying mechanism of DNA repair is still elusive. The histone methyltransferase KMT2D is a novel oncogene that associated with prostate carcinogenesis identified by us. Our recent studies indicated that the loss of KMT2D would downregulate the capacity of DNA damage repair and suppress the gene expression of ubiquitin ligases HERC2, which is the key member of ubiquitination dependent DNA double-strand breaks (DSBs) repair pathway. Therefore, we propose that in prostate cancer, KMT2D would activate the HERC2 transcription. The increased HERC2 expression would promote the ubiquitination dependent DSBs repair pathway and increase the prostate cancer cell resistance of DNA damage factors. Loss or inactivation of KMT2D would enhance the sensibility of DNA damage drugs. In this study, we hope to combine KMT2D knockdown/SET domain knockout cell model and KMT2D knockout mice model to analyze the correlation between KMT2D and DNA damage in prostate cancer and the mechanism of KMT2D regulating DNA repair via epigenetically activating HERC2. Furthermore, the organoid model derived from patients with advanced prostate cancer is used to evaluate the clinical value of KMT2D, providing new therapeutic methods for prostate cancer treatment.