HMGA Proteins in Cancer Biology

High mobility group A (HMGA) proteins are small, non-histone chromatin architectural factors that lack intrinsic transcriptional activity but reshape chromatin to facilitate or hinder access of regulatory proteins to DNA. Two paralogues, HMGA1 and HMGA2, are highly expressed during embryogenesis and silenced in most differentiated tissues, yet become aberrantly re-expressed in a wide spectrum of malignancies. In cancer cells, elevated HMGA levels drive proliferation, stemness and motility by orchestrating complex transcriptional networks, influencing pathways such as Wnt/β-catenin, FGF, Hippo and inflammatory signalling. HMGA proteins also promote epithelial–mesenchymal transition (EMT), extracellular matrix remodelling and the formation of a supportive stromal microenvironment, thereby enabling invasion, metastasis and resistance to therapy. Their expression correlates with poor prognosis across diverse tumour types, making HMGA proteins both biomarkers of aggressive disease and potential targets for novel therapeutic strategies.

Research from Nature Portfolio

Recent structural studies have resolved the atomic details of the first AT-hook motif of HMGA bound to an AT-rich DNA minor groove, revealing how this domain recognises specific sequences and induces moderate groove widening. Biophysical measurements of binding kinetics and thermodynamics have illuminated an entropy-driven 2:1 protein–DNA complex, while showing that small molecules can competitively inhibit AT-hook binding, offering a template for rational design of groove-binding inhibitors. Complementary functional investigations in intestinal systems have demonstrated that HMGA1 amplifies Wnt/β-catenin signalling, expanding both the intestinal stem cell compartment and Paneth cell niche. This activity underpins homeostatic renewal but, when deregulated, contributes to colorectal carcinogenesis, as HMGA1 upregulates Wnt receptors, downstream effectors and niche-supporting factors such as SOX9. These findings unify structural and cellular perspectives, highlighting HMGA as a master regulator of chromatin-mediated signalling in both normal tissue maintenance and tumour initiation.

HMGA Proteins in Cancer Biology publication trend

The graph below shows the total number of articles in hmga proteins in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

HMGA proteins: Small non-histone chromatin factors that modulate DNA architecture and transcriptional accessibility without direct enzymatic activity.

AT-hook: A short, positively charged peptide motif in HMGA that binds preferentially to AT-rich DNA minor grooves, altering local DNA conformation.

Chromatin remodelling: Dynamic reorganisation of nucleosome positioning or structure to regulate DNA accessibility for transcription, replication and repair.

Epithelial–mesenchymal transition (EMT): A cellular programme whereby epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

Desmoplastic stroma: A dense, fibrotic tissue microenvironment rich in activated fibroblasts and extracellular matrix that supports tumour progression.

References

1. HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. Journal of Clinical Investigation (2023).
2. Polypyrimidine tract-binding protein 3/insulin-like growth factor 2 mRNA-binding proteins 3/high-mobility group A1 axis promotes renal cancer growth and metastasis. iScience (2024).
3. Crystal structure of the HMGA AT-hook 1 domain bound to the minor groove of AT-rich DNA and inhibition by antikinetoplastid drugs. Scientific Reports (2024).
4. HMGA1 in cancer: Cancer classification by location. Journal of Cellular and Molecular Medicine (2019).
5. HMGA1 amplifies Wnt signalling and expands the intestinal stem cell compartment and Paneth cell niche. Nature Communications (2017).