Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression.

Abstract

High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating <i>Sox9</i>, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. <i>HMGA1</i> is also highly upregulated in colon cancer compared with nonmalignant epithelium and <i>SOX9</i> becomes overexpressed during colon carcinogenesis. Intriguingly, <i>HMGA1</i> is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that <i>HMGA1</i> overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. <i>Cancer Res; 78(8); 1890-7. ©2018 AACR</i>.