甲基化对雄激素转录活性调控的研究

在欧美男性中，前列腺癌所导致的死亡占肿瘤相关死亡的近三分之一。我国随着人口老龄化及饮食结构的改变, 前列腺癌的发病率也在正逐年上升。治疗前列腺癌最主要的手段就是通过手术或药物去势以阻断雄激素受体（AR）转导通路。因此, 深入研究AR的转录调控对于开发新的前列腺癌治疗药物以及指导临床进行个体化治疗都十分重要。本项目拟关注甲基化修饰对AR转录活性的调控。首先采用质谱鉴定AR的甲基化位点，并利用定点突变的方法研究甲基化位点的生物学功能。然后利用体外合成甲基化肽段沉淀结合定量蛋白质组学的方法明确此甲基化位点招募染色质修饰复合物的具体分子机制。最后将找到对应的甲基化酶，观察其特异性抑制剂对前列腺癌细胞生长等的影响。 本研究的结果将为利用此表观遗传调控酶既可以作用于组蛋白又可以调控AR的特点，开发针对前列腺癌新的治疗手段提供重要的理论以及实验室数据支撑。

Prostate cancer (PCa) accounts for 29% of total cancer cases among men in the United States and Europe. With the problem of population aging and changes in diet, the incidence of prostate cancer increases dramatically year by year in China. The standard treatment for prostate cancer (PCa) is surgical or medical castration to reduce circulating androgens (androgen deprivation therapy [ADT]) and suppress activity of the androgen receptor . Despite the critical role AR plays in PCa development and progression to CRPC, the mechanisms that regulate its transcriptional activity are not well understood. My objective is to improve the understanding of the mechanisms by which AR transcriptional activity is regulated by its methylation. The mass spectrometry will be employed to identify all the potential AR methylation sites. The sites will be mutate to Alanine to investigate their physiological function. And further, the corresponding methyltransferase will be identified and its specific inhibitor will be tested in the prostate cancer cell lines and Xenograft. We anticipate that the findings from this study will provide new approaches for targeting AR function in prostate cancer development and progression.