High Mobility Group Box Proteins in Cancer Biology

High Mobility Group Box (HMGB) proteins are ubiquitous non-histone chromatin regulators characterised by one or more HMG box DNA-binding domains and a flexible acidic tail. In normal cells they facilitate DNA bending, repair and the assembly of transcriptional complexes, but in cancer their expression and localisation are often dysregulated. Overexpression of HMGB1 and HMGB3 has been documented across a broad spectrum of malignancies, where intracellular HMGB proteins can promote malignant phenotypes, enhance stem-like properties and drive metabolic reprogramming. Extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP), engaging receptors such as RAGE, TLR4 or CXCR4 to stimulate angiogenesis, invasion and immune modulation within the tumour microenvironment. HMGB2 and HMGB3 similarly interact with key signalling cascades, notably MAPK/ERK and PI3K/AKT, to foster proliferation and metastasis. Conversely, manipulation of HMGB1 interactions or its post-translational modifications has emerged as a strategy to sensitise tumours to chemotherapy and radiotherapy. Together, these findings underscore the dual nuclear and extracellular roles of HMGB proteins in cancer development, progression and response to therapy, making them attractive targets for diagnostic and therapeutic intervention.

Research from Nature Portfolio

Recent studies have revealed that HMGB1 can form a dynamic heterocomplex with the chemokine CXCL12 via both structured HMG boxes and an intrinsically disordered acidic region. This fuzzy assembly diverges from classical rigid chemokine dimers and engages the CXCR4 receptor to potentiate cell signalling. Detailed structural and biophysical analyses demonstrated that the acidic tail of HMGB1 mediates multiple transient contacts with CXCL12, suggesting new modes of receptor activation. Interfering with this multivalent interface is proposed as a novel pharmacological approach to modulate inflammatory signals that are co-opted by tumours to support growth and immune evasion.

High Mobility Group Box Proteins in Cancer Biology publication trend

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

Technical terms

Heterocomplex: A dynamic assembly of two or more distinct proteins that interact transiently to fulfil a biological function.

Intrinsically Disordered Region (IDR): A segment of protein lacking a fixed three-dimensional structure, often mediating flexible interactions.

Damage-Associated Molecular Pattern (DAMP): Endogenous molecules released by stressed or dying cells that trigger immune responses.

Oligomerisation: The process by which protein monomers assemble into dimers, trimers or higher-order complexes.

Chemosensitivity: The susceptibility of cancer cells to the cytotoxic effects of chemotherapeutic drugs.

References

1. The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12. Nature Communications (2024).
2. Nuclear Fructose‐1,6‐Bisphosphate Inhibits Tumor Growth and Sensitizes Chemotherapy by Targeting HMGB1. Advanced Science (2023).
3. Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy. Biomaterials Research (2023).
4. HMGB3 promotes the malignant phenotypes and stemness of epithelial ovarian cancer through the MAPK/ERK signaling pathway. Cell Communication and Signaling (2023).