NFIB促进前列腺癌内分泌治疗耐药的机制及其作为耐药标志物的临床价值

晚期前列腺癌极易通过表型转化演变成CRPC而表现出内分泌治疗耐药，目前尚无精准预测前列腺癌内分泌治疗耐药的标志物而无法提前干预。我们研究发现，具有CRPC特性的组织与细胞中NFIB蛋白呈现高表达、高乙酰化与低泛素化状态，而NIFB的mRNA上调并不显著，干扰NFIB可使CRPC特性细胞向激素敏感型细胞表型转化。据此，我们推测NFIB乙酰化修饰抑制其泛素化降解维持其蛋白稳定在前列腺癌表型转化及内分泌治疗耐药中发挥重要作用。因此，本课题拟在前期研究基础上，揭示NFIB促进前列腺癌内分泌治疗耐药的关键分子事件，鉴定NFIB乙酰化位点及相关乙酰化酶，确证受乙酰化调控的泛素化位点，系统解析NFIB乙酰化修饰强化与Smads/FOXA1的结合诱发前列腺癌EMT介导内分泌治疗耐药的内在机制；探究NFIB在前列腺癌内分泌治疗耐药中的病理意义，为NFIB作为标志物预测内分泌治疗耐药提供实验基础和理论依据。

Advanced prostate cancer is very easily transformed into castration-resistant prostate cancer (CRPC) via phenotypic transformation, and exhibits endocrine therapy resistance. At present, there is no early intervention because of no precise biomarker for predicting the resistance of endocrine therapy in prostate cancer. In our previous research, it demonstrated that the protein of NFIB was highly expressed, highly acetylated and lowly ubiquitinated in tissue and cells with CRPC characteristics, however, the mRNA of NFIB was not upregulated significantly, and inhibiting the expression of NFIB can promote cells with CRPC characteristics transform into a hormone-sensitive phenotype, suggesting that NFIB acetylation inhibits its ubiquitination and maintains its stability are involved in prostate cancer phenotype transformation and endocrine therapy resistance. Therefore, on the basis of our previous research, the major objectives of the present proposal are to reveal the key molecular events of NFIB promoting the endocrine therapy resistance of prostate cancer, identify acetylation modification sites and related deacetylase of NFIB, furthermore, we will also identify ubiquitination sites of NFIB which regulated by acetylation, systematic analyze the intrinsic mechanism of acetylated NFIB enhanced binding to Smads/FOXA1 which induced EMT mediated endocrine therapy resistance in prostate cancer, and confirm the pathological significance of NFIB in endocrine therapy resistance of prostate cancer, which provides experimental and theoretical basis for NFIB as a biomarker to predict the endocrine therapy resistance of prostate cancer.