title: Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial-mesenchymal transition and metastasis in a YAP-independent manner.
abstract: Dysregulation of the Hippo pathway occurs in a variety of cancers and often correlates with a poor prognosis. To further explore the potential role of Hippo pathway dysregulation in tumor development and progression, we investigated its downstream transcription factor TEAD4 in colorectal cancer (CRC). Increased expression and nuclear localization of TEAD4 were found in a significant portion of CRC tissues, in association with metastasis and a poor prognosis. In CRC cells, TEAD4 knockdown induced the mesenchymal-epithelial transition and decreased cell mobility in vitro and metastasis in vivo. Microarray analysis revealed that TEAD4 promoted cell adhesion and upregulated the epithelial-mesenchymal transition-related transcriptome in CRC cells. Vimentin was identified as a new direct target gene mediating TEAD4 function in CRC cells, whereby forced vimentin expression markedly reversed TEAD4-knockdown-induced cell morphological changes and decreased mobility. Interestingly, rescued expression of both WT TEAD4 and a Y429H mutant can reverse the mesenchymal-epithelial transition and increase vimentin expression, cell mobility and metastatic potential in TEAD4-knockdown CRC cells. The discrepant expression of YAP and TEAD4 in CRC tissues, the rescue ability of TEAD4 mutant defect in YAP binding and no effect on vimentin expression by YAP knockdown in CRC cells, all implicated a YAP-independent manner of TEAD4 function in CRC. Furthermore, vimentin positively correlated and CDH1 reversely correlated with the level of TEAD4 in CRC tissues and xenograft tumors. Our results suggest that TEAD4 nuclear expression can serve as a biomarker for CRC progression and poor prognosis. The transcription factor TEAD4 regulates a pro-metastasis transcription program in a YAP-independent manner in CRC, thus providing a novel mechanism of TEAD4 transcriptional regulation and its oncogenic role in CRC, independently of the Hippo pathway.
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.|Center for Medical Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Mei
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: A
authors.initials: A
authors.lastname: Cui
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Shanghai Colorectal Cancer Research Center, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Cui
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D064593:Heterografts; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009124:Muscle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases