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.

中文翻译：

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YAP/TEAD4诱导的KIF4A导致食管鳞状细胞癌的进展和较差的预后


驱动蛋白家族成员 4A (KIF4A) 的异常表达与肿瘤进展相关，已在多种类型的癌症中被报道。然而，其在食管鳞状细胞癌（ESCC）中的表达和调节 KIF4A 转录的潜在分子机制仍不清楚。在这里，我们发现 KIF4A 高表达与 ESCC 患者的肿瘤分期和不良预后呈正相关。 KIF4A沉默显着抑制ESCC细胞的生长和迁移，阻滞细胞周期并诱导细胞凋亡。有趣的是，人食管鳞癌组织中KIF4A的表达与YAP的表达呈正相关。通过维替泊芬敲低 YAP 或破坏 YAP/TEAD4 相互作用可抑制 KIF4A 表达。此外，KIF4A 敲低显着抑制 YAP 过表达诱导的细胞生长。从机制上讲，YAP 通过 TEAD4 介导的与 KIF4A 启动子的直接结合来激活 KIF4A 转录表达。最后，KIF4A 敲低和维替泊芬治疗可协同抑制异种移植模型中的肿瘤生长。总之，这些结果表明，YAP/TEAD4 的新靶基因 KIF4A 可能是 ESCC 的进展和预后生物标志物。 KIF4A靶向药物联合YAP抑制剂可能是食管鳞癌的一种新的治疗策略。