title: The Wnt/β-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.
abstract: High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the β-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the β-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the β-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β-catenin/TCF-4 signalling.
authors.affiliation: Department of Chemistry, Physics, and Geology, Winthrop University, Rock Hill, SC 29733, USA.
authors.forename: Bethany M
authors.initials: BM
authors.lastname: Bush
authors.forename: Ashton T
authors.initials: AT
authors.lastname: Brock
authors.forename: Jiayue A
authors.initials: JA
authors.lastname: Deng
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Nelson
authors.forename: Takita Felder
authors.initials: TF
authors.lastname: Sumter
mesh_terms: D020121:5' Untranslated Regions; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D025742:HMGA1b Protein / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D025601:Adenomatous Polyposis Coli Protein; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D025742:HMGA1b Protein; D025741:HMGA1a Protein; D015032:Zinc