HMGA1 Activates FGFBP1 Transcription to Enhance Angiogenesis Induction and Tumor Progression via FGF2/FGFR1 Pathway

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). <i>HMGA1</i> silencing suppressed oncogenic properties <i>in vitro</i> and reduced tumor initiating cells in HNSCC xenograft mice. RNA sequencing revealed that HMGA1 regulated transcriptional networks involved in tumor progression and angiogenesis, including the <i>FGFBP1</i> gene. HMGA1 directly binds to the <i>FGFBP1</i> promoter to induce its expression. This upregulation increased secretion of FGFBP1's target, FGF2. Interestingly, disrupting FGFBP1 via gene silencing or the FGFR1 inhibitor PD166866 recapitulated phenotypes observed with <i>HMGA1</i> silencing. Blocking <i>HMGA1</i>, <i>FGFBP1</i>, or FGFR1 also reduced stromal formation and increased tumor necrosis. In human HNSCC, the combined analysis of HMGA1 and FGFBP1 provides a more detailed evaluation of patient prognosis. Our findings highlight a novel paradigm where HMGA1 and FGFBP1 drive tumor progression and angiogenesis, presenting them as potential therapeutic targets for HNSCC.