组蛋白H3K27去甲基化酶JMJD3在转移性及去势难治性前列腺癌中的功能及机制研究

Prostate cancer (PCa) has emerged as the most common malignant tumor of the urinary system in China. Despite recent progress, the underlying mechanism for how indolent tumors progress into metastatic PCa and how does PCa progresses to an androgen refractory state subsequent to androgen deprivation therapy (ADT) still remain to be define. Based on the functional library screen and patient sample analysis, we identified that Histone H3K27 demethylase JMJD3 might play a critical role in metastatic and Castrate Resistant Prostate Cancer (CRPC). Conditional ablation of JMJD3 in a PTEN prostate cancer model leads to a metastasis-prone cancer. Interestingly, we also identified that androgen signaling stimulates JMJD3 expression, suggesting that down-regulation of JMJD3 upon ADT might be a major reason to cause the development of CRPC. In this application, we propose to utilize the genetically engineered mouse models, a PTEN prostate cancer model and cell culture assay, together with patient sample analysis to define whether JMJD3 serves as an important epigenetic regulator to control the indolent tumors onto more aggressive tumors, which will lead to future development of potential biomarkers for clinical diagnosis. In addition, we will define whether JMJD3 plays a casual role in castration resistance. Further mechanistic investigation will also uncover the pivotal regulators and signal circuits involved in these two processes. Success accomplishment of the proposed goals will provide new insights on the etiology of this disease and develop new epigenetic therapies against disease progression.

前列腺癌已成为我国泌尿系统最常见的恶性肿瘤，其中高侵袭性转移和去势难治性是临床治疗和基础研究所面临的难题。本项目聚焦表观遗传调控在前列腺癌的转移和去势难治性前列腺癌形成中的生物学功能，已通过文库筛选以及病人样本数据分析的方法，发现组蛋白H3K27去甲基化酶JMJD3在前列腺癌转移以及去势难治性前列腺癌中发挥重要作用。JMJD3的体内敲除可以显著地促进前列腺癌在PTEN缺失小鼠中的发生发展及转移。更为重要的是内分泌治疗引起的JMJD3的下降可能是导致去势难治性前列腺癌产生的重要原因之一。因此，本项目研究中将继续以遗传小鼠作为模式生物，通过分子/细胞生物学，病人样品分析等实验手段，解析JMJD3在前列腺癌转移以及去势难治性前列腺癌中的功能及其分子机制。本项目的成功实施将有助于在表观遗传层面阐明前列腺癌高侵袭性转移和对雄激素剥夺疗法抵抗的分子机制，从而最终为临床诊断和治疗提供有益的思路和靶点。

前列腺癌是我国泌尿系统最常见的恶性肿瘤，其中高侵袭转移和内分泌治疗耐受是临床治疗和基础研究所面临的难题。本项目聚焦表观遗传调控因子JMJD3在前列腺癌转移和内分泌治疗耐受前列腺癌形成中的生物学功能。JMJD3是组蛋白H3K27去甲基化化酶。体内敲除JMJD3可以显著促进前列腺癌发展和转移。更为重要的是，JMJD3敲除还可以促进前列腺肿瘤耐受内分泌治疗。分子水平，JMJD3可以调控使AKT T308位点去磷酸化的磷酸酶PPP2CA。当JMJD3缺失后，招募到PPP2CA基因位点的JMJD3减少，导致该位点H3K27me3水平增加，PPP2CA的表达受到抑制。PPP2CA表达降低激活PI3K/AKT信号通路，从而促进内分泌治疗耐受的前列腺癌形成。本项目有助在表观遗传层面阐明前列腺癌对雄激素剥夺疗法抵抗的分子机制，最终为临床诊断和治疗提供有益的思路和靶点。