The Wnt/β‐catenin/TCF‐4 pathway upregulates HMGA1 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 signaling. In adenomatous polyposis coli (APCMin/+) mice, we observed significant upregulation of HMGA1 mRNA and protein in intestinal tumors when compared to normal intestinal mucosa. Conversely, restoration of Wnt signaling by zinc‐induction of wt‐APC resulted in HMGA1 downregulation 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 putative TCF‐4 binding elements (TBEs). We identified two functional 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 signaling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β‐catenin/TCF‐4 signaling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β‐ catenin/TCF‐4 signaling.