title: GATA6 promotes colon cancer cell invasion by regulating urokinase plasminogen activator gene expression.
abstract: GATA6 is a zinc finger transcription factor expressed in the colorectal epithelium. We have examined the expression of GATA6 in colon cancers and investigated the mechanisms by which GATA6 regulates colon cancer cell invasion. GATA6 was overexpressed in colorectal polyps and primary and metastatic tumors. GATA6 was strongly expressed in both the nuclear and cytoplasmic compartments of the colon cancer cells. GATA6 expression was upregulated in invasive HT29 and KM12L4 cells compared with the parental HT29 and KM12 cells and positively correlated with urokinase-type plasminogen activator (uPA) gene expression. Small interfering RNA (siRNA) knockdown of GATA6 resulted in reduced uPA gene expression and cell invasion. GATA6 bound to the uPA gene regulatory sequences in vivo and activated uPA promoter activity in vitro. uPA promoter deletion analysis indicated that the promoter proximal Sp1 sites were required for GATA6 activation of the uPA promoter. Accordingly, GATA6 physically associated with Sp1 and siRNA knockdown of Sp1 decreased GATA6 activation of the uPA promoter activity suggesting that Sp1 recruits GATA6 to the uPA promoter and mediates GATA6 induced activation of the uPA promoter activity. On the basis of our results, we conclude that GATA6 is an important regulator of uPA gene expression, and the dysregulated expression of GATA6 contributes to colorectal tumorigenesis and tumor invasion.
authors.affiliation: Michael E. DeBakey VA Medical Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. elaguli@bcm.edu
authors.forename: Narasimhaswamy S
authors.initials: NS
authors.lastname: Belaguli
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aftab
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rigi
authors.forename: Mao
authors.initials: M
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Albo
authors.forename: David H
authors.initials: DH
authors.lastname: Berger
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D016329:Sp1 Transcription Factor; D008156:Luciferases; D014568:Urokinase-Type Plasminogen Activator