School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences , East China Normal University, Shanghai, China.
Mol Carcinog. 2021 Jul;60(7):440-454. doi: 10.1002/mc.23303. Epub 2021 May 18.
Aberrant expression of kinesin family member 4A (KIF4A), which is associated with tumor progression, has been reported in several types of cancer. However, its expression and the underlying molecular mechanisms regulating the transcription of KIF4A in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that high KIF4A expression was positively correlated with tumor stage and poor prognosis in ESCC patients. KIF4A silencing significantly inhibited the growth and migration of ESCC cells, arrested cell cycle, and induced apoptosis. Interestingly, KIF4A expression was positively related to the expression of YAP in human ESCC tissues. YAP knockdown or disrupting YAP/TEAD4 interaction by verteporfin repressed KIF4A expression. Also, KIF4A knockdown significantly inhibited the cell growth induced by YAP overexpression. Mechanistically, YAP activated KIF4A transcriptional expression by TEAD4-mediated direct binding to KIF4A promoter. Finally, KIF4A knockdown and verteporfin treatment synergistically inhibited tumor growth in xenograft models. Together, these results indicated that KIF4A, a novel target gene of YAP/TEAD4, may be a progression and prognostic biomarker of ESCC. Targeting drugs for KIF4A combined with YAP inhibitor may be a novel therapeutic strategy for ESCC.
驱动蛋白家族成员 4A（KIF4A）的异常表达与肿瘤进展有关，已在几种类型的癌症中报道。然而，其在食管鳞状细胞癌（ESCC）中的表达及其转录的潜在分子机制仍很大程度上不清楚。在这里，我们发现高 KIF4A 表达与 ESCC 患者的肿瘤分期和预后不良呈正相关。KIF4A 沉默显著抑制 ESCC 细胞的生长和迁移，使细胞周期停滞，并诱导细胞凋亡。有趣的是，KIF4A 的表达与人类 ESCC 组织中 YAP 的表达呈正相关。YAP 敲低或通过 Verteporfin 破坏 YAP/TEAD4 相互作用抑制 KIF4A 的表达。此外，KIF4A 敲低显著抑制 YAP 过表达诱导的细胞生长。从机制上讲，YAP 通过 TEAD4 介导的直接结合到 KIF4A 启动子上激活 KIF4A 的转录表达。最后，KIF4A 敲低和 Verteporfin 治疗在异种移植模型中协同抑制肿瘤生长。总之，这些结果表明，KIF4A 是 YAP/TEAD4 的一个新的靶基因，可能是 ESCC 的进展和预后生物标志物。针对 KIF4A 的靶向药物与 YAP 抑制剂联合使用可能是 ESCC 的一种新的治疗策略。
