Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling.
Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling.
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Flightless I Homolog 通过靶向雄激素受体信号传导抑制前列腺癌的进展。
DOI：
10.1158/1078-0432.ccr-15-1632
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Chen Ke
中科院分区：
文献类型：
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作者：
Wang Tao;Song Wen;Chen Yuan;Chen Ruibao;Liu Zhuo;Wu Licheng;Li Mingchao;Yang Jun;Wang Liang;Liu Jihong;Ye Zhangqun;Wang Chenguang;Chen Ke
目的：Flightless I（FLII）是肌动蛋白重塑蛋白凝溶胶蛋白超家族成员，具有转录辅助调节功能。我们的目的是评估FLII在调节雄激素受体（AR）在前列腺癌progress.Experimental Design的肿瘤抑制功能：我们研究了FLII蛋白和mRNA的表达在临床前列腺癌标本免疫组化。进行Kaplan-Meier分析以评估与FLII和AR表达水平相关的疾病总生存率的差异。稳定表达FLII或shRNA敲低的前列腺癌细胞用于功能分析。免疫沉淀，荧光素酶报告，和免疫荧光染色试验进行检查FLII和AR之间的功能相互作用。结果：我们的临床基因表达阵列数据集的FLII的表达水平的分析表明，FLII的表达与前列腺癌患者的总生存率呈正相关，表现出高水平的AR表达。FLII的蛋白质和mRNA水平的检测显示FLII在人前列腺癌中的表达显著降低。AR和FLII通过AR的配体结合域（LBD）以配体依赖的方式形成复合物。随后，我们观察到FLII和配体之间与AR的竞争性结合。FLII抑制AR反式激活，减少AR核定位。此外，FLII通过AR依赖性信号传导促进去势敏感性和去势抵抗性前列腺癌细胞生长，并且在前列腺癌细胞中重新引入FLII使细胞对比卡鲁胺和恩杂鲁胺治疗敏感。©2015 AACR.
Purpose:Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression.Experimental Design:We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan–Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR.Results:Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment.Conclusions:FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies.Clin Cancer Res; 22(6); 1531–44. ©2015 AACR.