KMT2D调控AR转录、稳定性及核分布促进去势抵抗前列腺癌进展的作用和机制研究

去势抵抗阶段是前列腺癌临床治疗的难点，患者预后不良。在进展至去势抵抗前列腺癌（CRPC）过程中，雄激素受体（AR）会由于表达、结构和分布的改变，进而再次激活，对新一代抗雄治疗抵抗，如何继续抑制AR，是目前研究的热点和难点。组蛋白甲基化转移酶KMT2D是我们前期通过高通量测序筛选出的前列腺癌致病基因，预实验发现，KMT2D能够同时调控AR的转录、稳定性及核分布，从而增强CRPC中AR轴的活性。因此，我们认为KMT2D是介导前列腺癌由激素敏感到去势抵抗转换的关键致病基因。本项目拟在前期研究基础上，通过KMT2D沉默细胞模型和基因敲除小鼠，明确KMT2D对AR活性的调控作用；并综合RNA-seq、ChIP-seq和蛋白质组学分析，阐明KMT2D促进CRPC进展的分子机制；最后构建前列腺癌耐药细胞株，探索抑制KMT2D的治疗价值。从而在揭示分子机制的同时，为晚期前列腺癌的治疗提供新思路。

Castration-resistant prostate cancer (CRPC) is the major challenge of prostate cancer treatment. In this stage, the androgen receptor will reactivate due to the alteration of expression, structure, and intracellular location, and resistance to antiandrogens. How to understand the mechanism and further inhibit the reactivated of AR in CRPC is essential for CRPC treatment. The histone methyltransferase KMT2D is a high-frequency mutation gene identified by us by high-throughput gene sequencing. Subsequent studies confirmed that KMT2D is an important oncogene for prostate cancer progression. Here, our preliminary experiments indicated that KMT2D also involved in AR reactivation in CRPC. KMT2D could regulate both AR transcription activity, AR transcription activity, stability, and nuclear localization. Thus, KMT2D might lead to the cancer cell transition from hormone-sensitive to castration resistance. In this study, we will first identify the role of KMT2D in AR reactivation by KMT2D knockdown cell model and KMT2D knockout mice. Then, we will comprehensively explore the molecular mechanisms of KMT2D in AR activity regulation. Last, by established antiandrogen resistance cells, we will test whether KMT2D inhibition would re-sensitize the resistance cells to antiandrogens. Our study will further uncover the regulation of AR activity in CRPC, and identify a new approach to target the reactivated AR pathway.