HMGB1

Official Full Name

high mobility group box 1

Organism

Homo sapiens

GeneID

3146

Background

This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2015]

Synonyms

HMG1; HMG3; HMG-1; SBP-1;

Protein Sequence

MGKGDPKKPRGKMSSYAFFVQTCREEHKKKHPDASVNFSEFSKKCSERWKTMSAKEKGKFEDMAKADKARYEREMKTYIPPKGETKKKFKDPNAPKRPPSAFFLFCSEYRPKIKGEHPGLSIGDVAKKLGEMWNNTAADDKQPYEKKAAKLKEKYEKDIAAYRAKGKPDAAKKGVVKAEKSKKKKEEEEDEEDEEDEEEEEDEEDEDEEEDDDDE

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

High mobility group Box 1 protein (HMGB1) is a nuclear protein that acts as a DNA chaperone and participates in many activities in the nucleus, including replication, transcription, DNA repair and nucleosome assembly. Apart from its roles in the nucleus, HMGB1 can also translocate to the cytoplasm, where it can activate autophagy by interacting with beclin-1, and to the extracellular medium, where it acts as a DAMP (Damage Associated Molecular Pattern) molecule that alerts nearby cells and the immune system to immediate danger, triggering inflammation. HMGB1 has emerged as one of the main mediators in both acute and chronic inflammation, and thus plays a role in an impressive number of medical conditions.

Besides effects on immune cells, HMGB1 can modulate the activities of epithelial, hematopoietic and neuronal cells and mediate systemic effects such as fever, anorexia, and acute-phase responses. These activities reflect its function as an alarmin and its ability to engage diverse receptors including TLR2, TLR4, TLR9, CD24- Siglec-10 and RAGE (receptor for advanced glycation end products). In these interactions, post-translational modifications of HMGB1, including phosphorylation, acetylation, methylation and redox changes of cysteine residues, can influence the receptor interactions and downstream signaling events.

Figure 1. Signaling by HMGB1. (Harris H E, et al. 2012)

The Dual Roles of HMGB1 in Cancer

Over the past two decades, HMGB1 has been demonstrated as one of the major players in many cancers including colon, breast, lung, kidney, stomach, prostate, cervical, skin, pancreatic, liver, bone, and blood cancer. HMGB1 acts as both a tumor suppressor and an oncogenic factor in tumorigenesis and cancer therapy relying on the context and the study conditions, as well as HMGB1 location and modification.

The tumor microenvironment consists of tumor cells and nontumor cells, including multiple immune cells. HMGB1 can be released, including through autocrine from the tumor cells and the surrounding cells under hypoxia or other environmental stimuli. Extracellular HMGB1 mediates communication between cells in the tumor microenvironment by various receptors (e.g., TLR4 and RAGE), which contributes to tumor growth and spreads by several mechanisms including sustenance of the inflammatory microenvironment, fulfillment of metabolic requirements, promotion of invasion and metastasis, inhibition of antitumor immunity, and promotion of angiogenesis. Therefore, inhibition of HMGB1 release and activity can block tumor growth and development.

Several studies show that intracellular HMGB1 may be a tumor suppressor. For example, nuclear HMGB1 binds to tumor suppressor RB, which results in RB-dependent G1 arrest and apoptosis induction and prevents tumorigenicity in breast cancer cells in vitro and in vivo. Nuclear HMGB1 is an important architectural factor with DNA chaperone activity. Loss of HMGB1 results in genome instability with telomere shortening, which is a major driving force in tumorigenesis. In addition, recent studies suggest that deficiencies of autophagy gene (e.g., ATG5, Beclin-1, UVRAG, Bif-1) increase tumorigenesis due to genome instability, inflammation, an organelle injury. Given that HMGB1 is a positive regulator of autophagy, HMGB1 deficiency causing autophagy dysfunction may lead to genome instability and inflammation, which promotes tumorigenesis.

Figure 2. The dual roles of HMGB1 in cancer. (Kang R, et al. 2013)

HMGB1's Protective Roles in Anticancer Therapy

HMGB1-mediated immunogenic cell death (ICD) contributes to immune-mediated eradication of tumors during chemotherapy or radiotherapy. ICD is characterized by the release of dying cancer cells or cell surface exposure of DAMPs (e.g., calreticulin, HSPs, HMGB1, and ATP), which are helpful for the maturation, antigen uptake, and presentation of dendritic cells and serve as powerful immunologic adjuvants to active CTL response. Autophagy-mediated ATP release also contributes to ICD development. Blocking the HMGB1-TLR4 pathway inhibits ICD-associated anticancer immune responses upon chemotherapy in vitro and in vivo. However, HMGB1 released from necrotic cancer cells treated with chemotherapy enhances regrowth and metastasis of remnant cancer cells in a RAGE-dependent way. Therefore, blocking HMGB1–RAGE signaling increases the effectiveness of chemotherapy.

HMGB1's Negative Roles in Anticancer Therapy

Induction of cell death and inhibition of cell growth are the main targets of cancer therapy. Many studies have shown that suppression of HMGB1 expression by RNA interference increased the anticancer activity of cytotoxic agents, whereas overexpression of HMGB1 expression by gene transfection increased drug resistance. HMGB1 expression regulates chemotherapeutic response and resistance by interfering with autophagy and the apoptotic pathway. HMGB1 increases prosurvival autophagy in a Beclin 1-dependent way in chemotherapy, whereas HMGB1 inhibits both extrinsic and intrinsic programmed cell death/apoptosis in a caspase-dependent way in cancer cells. In some cases, knockout HMGB1 in fibroblasts inhibits antimetabolite drug-induced apoptosis, indicating that HMGB1 plays a distinct role in apoptosis depending on cell types. The cross-talk between apoptosis and autophagy regulates cell death and determines cell fate in anticancer therapy.

References:

Harris H E, et al. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nature Reviews Rheumatology, 2012, 8(4): 195.
Venereau E, et al. HMGB1 as biomarker and drug target. Pharmacological research, 2016, 111: 534-544.
Kang R, et al. HMGB1 in cancer: good, bad, or both?. Clinical cancer research, 2013, 19(15): 4046-4057.
Kang R, et al. HMGB1 in health and disease. Molecular aspects of medicine, 2014, 40: 1-116.

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