ERG介导组蛋白修饰调控SLP2促进EMT在前列腺癌转移中的作用及机制

Lymph node metastasis is the primary cause of mortality from prostate cancer (PCa). In our previous studies, we showed that ERG overexpression induced by TMPRSS2-ERG gene fusion is a critical molecular event in PCa early metastasis. However, the molecular mechanisms of ERG initiating PCa metastasis remains obscure. Our recent investigations also found: (1) SLP2 expression was significantly higher in patients with TMPRSS2-ERG positive PCa. There were significant differences in SLP2 expression between lymph node positive and negative PCa. Subsequent functional studies demonstrated that SLP2 contributes to PCa metastasis via promoting epithelial-mesenchymal transition (EMT). (2) There is a positive correlation between relative SLP2 expression and its corresponding ERG expression in PCa cells. No direct interaction between ERG and SLP2 proteins and no direct binding between SLP2 promoter and ERG were found. (3) There are binding sites in SLP2 promoter for histones. The transcription activity of SLP2 could possibly be regulated by histone modifications. Herein, based on these findings and the close correlation between ERG and epigenetic regulation, we speculate and present the novel mechanisms underlying ERG-inducing lymph node metastasis in PCa: ERG overexpression could enhance the activity of histone modifications factor via MAPK signal pathway. Subsequently, the transcription activity of SLP2 is enhanced by histone modifications in its promoter, thus contributes to EMT and PCa metastasis. The present study would elucidate the mechanisms of SLP2 transcription activation induced by ERG-mediated epigenetic variation. Our results may provide novel and imperative molecular targets for the intervention of PCa metastasis.

淋巴转移是前列腺癌(PCa)致死的重要因素。我们前期研究证实TMPRSS2-ERG基因融合诱导ERG过表达是PCa早期转移的关键分子事件，但其机制不明。结合近期研究：SLP2在ERG阳/阴性PCa之间及淋巴结阳/阴性PCa之间均存在差异表达，SLP2通过促进上皮间质转化(EMT)增强PCa转移能力；PCa细胞中ERG与SLP2表达成正相关，ERG与SLP2蛋白或其启动子不发生直接作用；SLP2启动子区存在组蛋白结合位点，可能通过组蛋白修饰调控其转录活性；同时，鉴于ERG与表观遗传学调控的密切关联，我们提出ERG促进PCa淋巴转移新机制：过表达ERG通过MAPK途径，激活组蛋白修饰物活性，继而影响SLP2启动子区组蛋白状态，增强其转录活性，促进癌细胞EMT和转移。本项目拟围绕上游ERG过表达所致表观遗传学改变，阐明组蛋白修饰调控SLP2转录促进EMT的机理，为干预PCa转移提供重要分子靶点。

淋巴转移是前列腺癌致死的重要因素，淋巴转移阳性前列腺癌根治术后生化复发率约为45%。本项目在前期工作基础上，紧紧围绕 “过表达的ERG通过介导表观遗传修饰调控SLP2促进前列腺癌EMT”这一科学问题，从ERG的新调控机制入手，分别在分子机制水平，证实了ERG通过组蛋白表观遗传修饰增强SLP2转录活性。体外实验水平，进一步明确在前列腺癌中ERG异常表达促进SLP2高表达，从而导致前列腺癌细胞EMT和侵袭性伪足形成能力；在动物实验水平，确定ERG异常表达对前列腺癌细胞体内转移能力的影响；在临床水平，发现和证实ERG/SLP2表达在前列腺癌淋巴转移和预后预测中具有重要价值，项目按照计划顺利完成。共发表2篇论文，其中SCI论著1篇（IF 11.238），国内核心期刊论著1篇。