Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 "transcriptome" is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer's disease and type-2 diabetes.Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.
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.
