High-mobility group box 1 and cancer

Abstract

High-mobility group box 1 protein (HMGB1), a chromatin associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is an evolutionarily ancient and critical regulator of cell death and survival. Overexpression of HMGB1 is associated with each of the hallmarks of cancer including unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. Our studies and those of our colleagues suggest that HMGB1 is central to cancer (abnormal wound healing) and many of the findings in normal wound healing as well. Here, we focus on the role of HMGB1 in cancer, the mechanisms by which it contributes to carcinogenesis, and therapeutic strategies based on targeting HMGB1.

Figure 1. Intranuclear and Extranuclear Functions of HMGB1

The high-mobility group box 1 protein (HMGB1) is present in almost all metazoans and plants. The expression of HMGB1 is regulated by transcription factors including p53, c-Myc, and KLF4 in individual cell types. As a DNA chaperone, HMGB1 participates in DNA replication, recombination, transcription and repair. HMGB1 also been interacts with and enhances the activities of a number of transcription factors implicated in cancer development, including p53, p73, the retinoblastoma protein (RB), members of the Rel/NF-κB family, and nuclear hormone receptors including the estrogen receptor (ER). Cytosolic HMGB1 promotes autophagy and, in particular, mitophagy. HMGB1 is passively released from necrotic cells and is actively secreted by inflammatory cells, binding with high affinity to several receptors including the receptor for advanced glycation end products (RAGE), Toll-like receptors (TLR)-2, TLR-4, TLR-9, and, as a negative signaling molecule, CD24, mediating the response to infection, immunity, autoimmunity, chemotaxis, cell proliferation and tissue regeneration.

Figure 2. Role of HMGB1 in Cancer

In cancer, overexpression of HMGB1 is associated with each of the hallmarks of cancer including unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis.