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The Wnt/β‐catenin/T‐cell factor 4 pathway up‐regulates high‐mobility group A1 expression in colon cancer
Author(s) -
Bush Bethany M.,
Brock Ashton T.,
Deng Jiayue A.,
Nelson Ronald A.,
Sumter Takita Felder
Publication year - 2013
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.2876
Subject(s) - wnt signaling pathway , adenomatous polyposis coli , biology , catenin , cancer research , beta catenin , microbiology and biotechnology , signal transduction , colorectal cancer , cancer , genetics
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. Copyright © 2012 John Wiley & Sons, Ltd.