ZEB2 upregulates integrin α5 expression through cooperation with Sp1 to induce invasion during epithelial-mesenchymal transition of human cancer cells.
Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion, metastasis, embryonic development and wound healing. ZEB2 is a transcription factor involved in EMT that represses E-cadherin transcription. Although E-cadherin downregulation is a major event during EMT and tumor progression, E-cadherin reduction is probably not sufficient for full invasiveness. The mechanisms by which E-cadherin transcriptional repressors induce mesenchymal genes during EMT remain largely unknown. Here, we investigated the role of ZEB2 in the induction of integrin α5 during cancer EMT and its underlying mechanism. In human cancer cells, ZEB2 was found to directly upregulate integrin α5 transcription in a manner that is independent of the regulation of E-cadherin expression. Conversely, depletion of ZEB2 by small interfering RNA suppressed integrin α5 expression, leading to reduced invasion. Suppression of integrin α5 inhibited cancer cell invasion, suggesting an important role for integrin α5 in cancer progression. Furthermore, ZEB2 was found to activate the integrin α5 and vimentin promoters by interacting with and activating the transcription factor Sp1, suggesting that cooperation between ZEB2 and Sp1 represents a novel mechanism of mesenchymal gene activation during EMT. These findings increase our understanding of the pathways beyond E-cadherin reduction that regulate mesenchymal gene expression during EMT and cancer progression.
Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejon 305-806, Korea.
Eun-Hee
EH
Nam
Yunhee
Y
Lee
Young-Kyu
YK
Park
Jung Weon
JW
Lee
Semi
S
Kim
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D014746:Vimentin / Q000096:biosynthesis / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2
D015820:Cadherins; D018398:Homeodomain Proteins; D039482:Integrin alpha5; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014746:Vimentin; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2