Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer
Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer
复制标题
靶向 KIF4A/AR 轴逆转去势抵抗性前列腺癌的内分泌治疗抵抗
DOI：
10.1158/1078-0432.ccr-19-0396
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发表时间：
2020-03-01
影响因子：
11.5
通讯作者：
Zhang, Xiaoping
中科院分区：
文献类型：
--
作者：
Cao, Qi;Song, Zhengshuai;Zhang, Xiaoping
目的：新出现的证据表明，去势抵抗性前列腺癌（CRPC）通常由组成性活性雄激素受体（AR）或其V7剪接变体（AR-V7）驱动，并且通常对内分泌治疗产生抗性。这项工作的目的是评估驱动蛋白KIF 4A在前列腺癌内分泌治疗抵抗中调节AR/AR-V7的功能。实验设计：我们通过IHC检测临床前列腺癌标本中KIF 4A的表达。通过qRT-PCR、免疫印迹分析、免疫沉淀、荧光素酶报告基因和染色质免疫沉淀（ChIP）试验研究了调节途径。在细胞系和异种移植模型中进行了一系列功能分析。结果如下：对前列腺癌患者KIF 4A蛋白和mRNA水平的检测显示，KIF 4A表达的增加与雄激素受体（AR）水平呈正相关。肿瘤KIF 4A表达较低的患者的总生存期和无病生存期有所改善。从机制上讲，KIF 4A和AR在前列腺癌中形成了一个自动调节的正反馈环：KIF 4A结合AR和AR-V7，并阻止CHIP介导的AR和AR-V7降解; AR结合KIF 4A的启动子区，并激活其转录。KIF 4A通过AR和AR-V7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。此外，KIF 4A表达在恩杂鲁胺耐药前列腺癌细胞中上调，KIF 4A敲低有效逆转恩杂鲁胺耐药并增强CRPC细胞对内分泌治疗的敏感性。结论：这些发现表明，KIF 4A在CRPC的进展中起着重要作用，并且是CRPC对内分泌治疗耐药的关键决定因素。
Purpose: Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. Experimental Design: We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models. Results: Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through AR- and AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy. Conclusions: These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.