title: Twist1 and AP-1 cooperatively upregulate integrin α5 expression to induce invasion and the epithelial-mesenchymal transition.
abstract: Epithelial-mesenchymal transition (EMT) is an important process implicated in tumor invasion and metastasis. Twist1 is a transcription factor that induces EMT, including E-cadherin suppression and cancer cell migration and invasion; hence it promotes cancer metastasis. Twist1 directly or indirectly regulates the expression of various genes and cellular functions involved in cancer progression. However, the underlying mechanisms remain largely unknown. In this study, we investigated the molecular basis for Twist1-mediated invasion and EMT. In human cancer cells, Twist1 was found to directly upregulate transcription of the mesenchymal gene integrin α5 in an E-box-independent, but activating protein-1 (AP-1) element-dependent, manner. Twist1 activated the integrin α5 promoter by interacting with and activating the transcription factor AP-1, composed of c-Jun and activating transcription factor-2 (ATF-2); it also enhanced the nuclear presence of ATF-2. AP-1 was critical for Twist1-induced cancer cell invasion, primarily through the induction of integrin α5, which activated c-Jun N-terminal kinase and focal adhesion kinase-signaling activities. Using data from The Cancer Genome Atlas, we found that Twist1 expression positively correlates with integrin α5 expression in human colorectal cancers. These findings suggest that cooperation between Twist1 and AP-1 represents a novel mechanism for EMT and tumor invasiveness. This study supports further investigation into the molecular basis underlying the diverse Twist1-mediated functions that occur during tumor progression.
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Nam
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea, Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea, Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea and.
authors.forename: Byul
authors.initials: B
authors.lastname: Moon
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea, Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea, Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea and semikim@kribb.re.kr.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D039482:Integrin alpha5; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D018808:Transcription Factor AP-1; D051879:Twist-Related Protein 1; D048031:JNK Mitogen-Activated Protein Kinases