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 Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 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 HMGA1 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. Cancer Res; 78(8); 1890-7. ©2018 AACR.

Figure 1.

HMGA1 remodels chromatin to drive developmental transcriptional networks in cancer and stem cells. A, HMGA1 binds to DNA, “opens” chromatin, and recruits transcriptional complexes to activate Wnt genes and other developmental transcriptional networks. B, In ESCs and adult stem cells, HMGA1 is highly expressed, where it fosters plasticity, regenerative function, self-renewal, niche building, and proliferation, whereas HMGA1 is low or silenced in differentiated cells. Data in murine and human adult stem cells suggest that HMGA1/Hmga1 levels decline with aging, which could contribute to decreased regenerative function and tissue attrition. C, In contrast, HMGA1 is induced by many factors, which, in the setting of an aged and/or mutated genome, could drive plasticity, EMT, neoplastic transformation, and cancer stem cell properties. It may also help to establish a “cancer cell niche.” This model predicts that tightly regulated HMGA1 is essential for normal regenerative function, and possibly “normal” aging, whereas deregulated overexpression fosters tumor initiation and progression.

Figure 2.

Tightly regulated HMGA1 fosters balanced self-renewal and “builds a niche” in normal intestinal homeostasis (left). In contrast, deregulated, overexpressed HMGA1 drives aberrant plasticity, EMT, cancer stem cell properties, proliferation/polyposis, and may also “build” a “cancer stem cell niche” through Paneth cell metaplasia in the colon (right). Proteins encoded by genes that are upregulated in Hmga1 transgenic Lgr5⁺ ISCs are indicated by red text. (Figure adapted from reference 51).