PHF8增强beta-catenin/Snail2信号在去势诱导的前列腺癌上皮间质转化中的作用机制研究

Multiple lines of evidence suggest that castration treatment-induced Epithelial-mesenchymal transition (EMT) of prostate cancer plays crucial roles in the pathogenesis of castration resistant prostate cancer (CPRC) and disease progression. Previous studies demonstrated that the activation of β-catenin mediated snail2 signaling might be the main event during EMT process after long time of androgen deprivation therapy (ADT). However, the underlying molecular mechanism by which castration treatment activates β-catenin/snail2 signaling still remains unclear. Our previous findings showed that PHF8 is upregulated by HIFs （hypoxia inducible factors）in the condition of hypoxia induced by ADT. PHF8 knockdown could repress castration-induced transcription of snail2 and EMT process. Taken all together, we hypothesized that PHF8, as a ‘switch molecule’, might play an important regulatory role in the EMT process induced by ADT via activating β-catenin/snail2 signaling. In this study, by using prostate cancer cell lines, xenografts and a new mice model of prostatic carcinoma with PHF8 knockout background (TRAMP/PHF8-/Y) by crossing TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) with PHF8 knockout mice, we will investigate how PHF8 regulates the expressions of snail2, as well as their effects on ADT-induced EMT process. These studies will shed a new insight into understanding the molecular mechanisms underlying the development of CRPC as well as looking for the potential molecular target for therapeutic intervention of CRPC, which is of very important scientific significance as well as clinical value.

去势治疗诱导的上皮间质转化（Epithelial-mesenchymal transition, EMT）改变是前列腺癌CRPC发生及疾病进展重要原因。研究证实，β-catenin/snail2信号激活在其中发挥关键调节作用。但去势治疗激活β-catenin/snail2信号的具体机制尚不清楚。我们既往研究发现，PHF8受去势诱导的缺氧调控，敲低PHF8显著抑制去势诱导的snail2的转录活化及EMT改变。结合以往及我们的前期研究，我们推测：PHF8作为去势诱导的β-catenin/snail2信号激活的“开关”调节分子，在前列腺癌上皮间质转化中发挥重要作用。本项目拟以前列腺癌细胞、裸鼠移植瘤及PHF8基因敲除前列腺癌小鼠模型为研究对象，研究PHF8对β-catenin/snail2信号通路的调节机制及其在去势诱导的前列腺癌EMT中的作用。研究结果将揭示前列腺癌EMT新的调控机制，提高前列腺癌治疗效果，具有重要科学意义及潜在的临床应用价值。

去势治疗诱导的上皮间质转化（Epithelial-mesenchymal transition, EMT）改变是前列腺癌CRPC发生及疾病进展转移的重要原因。既往研究证实，β-catenin信号激活在其中发挥关键调节作用。但去势治疗激活β-catenin信号的具体机制尚不清楚。我们既往研究发现，PHF8受去势诱导的缺氧调控，在本研究中我们主要聚焦于揭示PHF8对去势诱导的前列腺癌EMT和转移调控。我们的研究结果发现：PHF8作为去势诱导的β-catenin信号激活的“开关”调节分子，在前列腺癌上皮间质转化中发挥重要作用。在TRAMP小鼠模型中，敲除PHF8后，小鼠在37和42周均不再发生转移；在细胞系中敲低PHF8后，细胞的生长、增殖、侵袭和迁移能力也明显受到抑制；进一步研究发现PHF8敲低后间质的marker明显下调，而上皮标志物E-cadherin明显上调，提示敲低PHF8后抑制EMT进展；机制上，我们发现PHF8与β-catenin相互作用调控β-catenin信号，从而影响EMT进展。更重要的是，我们还发现PHF8在前列腺癌神经内分泌分化中发挥重要作用，PHF8与β-catenin相互作用，通过表观遗传调控机制促进FOXA2转录，进而促进前列腺癌神经内分泌分化。本项目研究结果揭示前列腺癌转移进展和神经内分泌分化的重要分子机制，靶向PHF8/β-catenin信号通路可能成为前列腺癌治疗新策略，对提高前列腺癌治疗效果，具有重要科学意义及潜在的临床应用价值。

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