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.
High Mobility Group A1 (HMGA1) encodes proteins that act as mediators in viral integration, chromatin modification, neoplastic transformation, and metastatic progression. Because hmga1 expression is overexpressed in most cancers and has known interactions with several Wnt/β‐catenin‐responsive genes, we explored the involvement of HMGA1 in colorectal cancer. Apc mutations occur in most colorectal cancers and are associated with the mobilization of the β‐catenin/Tcf‐4 transcriptional complex. In adenomatous polyposis coli (Apc)(Min/+) mice expressing truncated Apc, we observed 9‐fold greater HMGA1 mRNA levels relative to mice bearing wild‐type Apc. HMGA1 protein levels were also significantly elevated in Apc(Min/+)intestinal tumors. Sequence analysis of the 5′‐flanking sequence of hmga1 identified a functional Tcf‐4 binding element (TBEs) that specifically binds Tcf‐4 in vitro and in vivo suggesting that hmga1 is a downstream target of the β‐catenin/Tcf‐4 signaling pathway. These findings will be further substantiated by transcription assays to evaluate the impact of Tcf‐4 and β‐catenin expression on hmga1 promoter activity. The results confirm previous work identifying hmga1 as a downstream target of the β‐catenin/Tcf‐4 complex and provide a new target for the development of therapies aimed at treating colorectal cancer. This research is supported by NIH 2P20 RR016461‐05, 1R15CA137520‐01 and NSF MCB055810542242.
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.
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