TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1

TEAD4 (TEA domain family member 4) was recently revealed as an oncogenic character in tumorigenesis. However, its role remains unclear in colorectal tumorigenesis. Here, we firstly found that the expression level of TEAD4 was significantly elevated in clinical samples of colorectal adenomas (CRA) and correlated with the size and histological type of CRA. Moreover, patients with higher TEAD4 expression in normal colon mucosa are more prone to be recurrent after polypectomy. TEAD4 knockdown significantly inhibited colorectal cell proliferation in vitro and suppressed tumor growth in vivo. RNA-seq and GSEA analysis reveals TEAD4 can probably regulate Hippo pathway and further experiment confirm the downstream target gene YAP1. The subsequent ChIP-qPCR and luciferase report assay indicated that TEAD4 regulated YAP1 by direct binding and transcriptional activation. In summary, our study reveals that TEAD4 plays an important tumor-promoting role in colorectal cancer by directly targeting the YAP1, thus we suggests TEAD4 may be used as a novel biomarker in colorectal tumorigenesis and provides TEAD4/YAP1 axis as a potential therapeutic option for colorectal cancer.TEAD4（TEA结构域家族成员4）近期被证实具有致癌特性，但其在结直肠肿瘤发生中的作用仍有待阐明。本研究首次发现，TEAD4在结直肠腺瘤（colorectal adenomas, CRA）临床样本中的表达水平显著升高，且与结直肠腺瘤的大小及组织学类型密切相关。此外，正常结肠黏膜中TEAD4高表达的患者，在息肉切除术后更易复发。敲低TEAD4可显著抑制结直肠癌细胞的体外增殖，并在体内抑制肿瘤生长。RNA测序（RNA-seq）与基因集富集分析（GSEA，Gene Set Enrichment Analysis）结果显示，TEAD4可能调控Hippo信号通路，后续实验进一步证实了其下游靶基因为YAP1（Yes相关蛋白1，Yes-associated protein 1）。后续的染色质免疫沉淀定量PCR（ChIP-qPCR，Chromatin Immunoprecipitation quantitative PCR）与荧光素酶报告基因实验表明，TEAD4可通过直接结合并转录激活的方式调控YAP1。综上，本研究揭示TEAD4通过直接靶向YAP1在结直肠癌中发挥重要的促肿瘤作用，提示TEAD4可作为结直肠肿瘤发生的新型生物标志物，并为结直肠癌的治疗提供了TEAD4/YAP1信号轴这一潜在治疗策略。