表观遗传调控因子EZH2在神经内分泌前列腺癌发生中的作用及机制研究

Patients with metastatic prostate cancer are typically managed with androgen-deprivation therapy (ADT). Although most patients initially respond to treatment, many eventually develop castration-resistant prostate cancer. Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of castration-resistant prostate cancer, which is often derived from prostate cancer cell neuroendocrine differentiation (NED). It is estimated that at least 25% of patients with lethal castration-resistant prostate cancer may eventually develop this type of highly aggressive NEPC. NEPC has a dismal outcome with an average survival of less than 1 year, shows less response to radio-chemotherapy. Recent findings implicate that enhancer of zeste homolog 2 (EZH2) is overexpressed in a wide range of cancer types, and associated with tumor progression and worse prognosis. To our knowledge, the role of EZH2 in NEPC develogment has not been investigated. In our preliminary studies, we found that EZH2 is highly expressed in the NEPC tissue, it is upregulated after ADT induced prostate cancer cell line (LNCaP) NED. Inhibition of the EZH2 could inhibit ADT induced LNCaP cell NED. Thus, we hypothesize that EZH2 is a critical epigenetic regulator of NEPC. To test this hypothesis, we will investigate the molecular mechanism of EZH2 mediated prostate cancer cell NED. The expected results of this study will provide a theoretical basis for NEPC development, and provide new ideas to explore the development and application of anticancer drugs for NEPC.

转移性前列腺癌接受去势治疗（ADT）后将逐渐发展为去势抵抗性前列腺癌（CRPC）。神经内分泌前列腺癌（NEPC）是CRPC的预后极差亚型, 多由前列腺癌细胞发生神经内分泌分化（NED）引起，目前治疗方法疗效较差，平均生存期不到1年，约占因CRPC死亡患者的25％。EZH2与多种恶性肿瘤的不良预后显著相关，但在NEPC发生中的作用尚无报道。我们在前期研究中发现EZH2在NEPC中高表达；ADT诱导前列腺癌细胞发生NED后EZH2表达显著升高；EZH2抑制剂可显著抑制ADT诱导NED。因此，我们推测EZH2是调控ADT诱导NEPC发生的关键信号分子。本项目拟通过临床样本、体外细胞实验及小鼠模型，探讨EZH2在ADT诱导NED过程中介导基因沉默的关键作用位点及下游关键靶基因的变化，明确其作用及分子机制。本研究将为NEPC发生机制提供新的理论依据，同时为NEPC治疗药物的开发与应用提供新的思路。

前列腺癌是男泌尿生殖系统常见肿瘤之一，大多数前列腺癌发现时即为转移性前列腺癌（mPCA）。转移性前列腺癌接受去势治疗（ADT）后将逐渐发展为去势抵抗性前列腺癌（CRPC）。神经内分泌前列腺癌（NEPC）是CRPC的预后极差亚型, 多由前列腺癌细胞发生神经内分泌分化（NED）引起，目前治疗方法疗效较差。目前关于NEPC的起源尚无明确结论，有假说提出去势治疗等治疗手段可诱导前列腺癌细胞发生神经内分泌分化。目前报道表明Zeste 基因增强子同源物 2（EZH2）与多种恶性肿瘤的不良预后显著相关。在本课题中，我们通过研究中发现EZH2在NEPC中高表达；在 NEPC 伴有前列腺癌的患者中， NEPC 组织的 EZH2 表达显著高于前列腺癌组织ADT诱导前列腺癌细胞发生NED后EZH2表达显著升高；EZH2抑制剂可显著抑制ADT诱导NED，加入 EZH2特异性小分子抑制剂 GSK343 可以显著抑制 NSE 表达， 即 LNCaP 细胞 NED 的发生；与此同时，我们发现单独过表达EZH2或MYCN并不能诱导LNCaP前列腺癌细胞系发生神经内分泌分化，而同时过表达MYCN及EZH2则可以通过其相互作用可以诱导LNCaP前列腺癌细胞系发生神经内分泌分化，且MYCN及EZH2同时过表达可以诱导PC-3前列腺癌细胞系发生神经内分泌分化后，前列腺癌细胞的凋亡比例下降，细胞的迁移以及侵袭能力显著上升，说明MYCN及EZH2在前列腺癌神经内分泌分化过程中，可能发挥了重要作用，并通过前列腺癌细胞迁移以及侵袭能力显著上升而促进前列腺癌发生转移。总之，本研究将为NEPC发生机制提供新的理论依据，同时为NEPC治疗药物的开发与应用提供新的思路。