HMGB1 in cancer: good, bad, or both?

Abstract

Forty years ago, high mobility group box 1 (HMGB1) was discovered in calf thymus and named according to its electrophoretic mobility in polyacrylamide gels. Now, we know that HMGB1 performs dual functions. Inside the cell, HMGB1 is a highly conserved chromosomal protein acting as a DNA chaperone. Outside of the cell, HMGB1 is a prototypical damage-associated molecular pattern, acting with cytokines, chemokines, and growth factors. During tumor development and in cancer therapy, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways, including inflammation, immunity, genome stability, proliferation, metastasis, metabolism, apoptosis, and autophagy. Here, we review the current knowledge of both HMGB1's oncogenic and tumor-suppressive roles and the potential strategies that target HMGB1 for the prevention and treatment of cancer.

Figure 1. Structure and function of HMGB1

(A) HMGB1 is structurally composed of three different domains: two homologous DNA-binding domains (box A and box B) and a negatively charged C-terminal domain. Residues 150–183 are responsible for binding to RAGE, whereas residues 89–108 and residues 7–74 are responsible for binding to TLR4 and p53 transactivation domain, respectively. Two nuclear localization signals (NLS1 and NLS2) control nuclear transport of HMGB1. In addition, HMGB1 contains three redox-sensitive cysteine residues (C23, C45 and C106), which are important for HMGB1 activity. (B) HMGB1 has multiple roles based on its location, as indicated.

Figure 2. The dual roles of HMGB1 in cancer

(A) The hallmarks of cancer comprise ten biological capabilities acquired during the multistep development of human tumors Deregulation of HMGB1 is associated with the hallmarks of cancer. Figure modified from Hanahan and Weinberg (4). (B) HMGB1 acts as an anti- or pro-tumor protein in tumor development and therapy. Extracellular HMGB1 promotes proliferation, inflammation, energy metabolism, and angiogenesis, and inhibits host anti-cancer immunity, which contributes to tumorigenesis. In contrast, extracellular-HMGB1 is important for the immunogenic cell death (ICD) of cancer cells and stimulates antitumor immunity response during chemotherapy or radiotherapy. HMGB1’s binding to TLR4 increases antitumor immunity, whereas binding to TIM-3 inhibits antitumor immunity in DCs. Intracellular HMGB1 prevents genome instability and enhances RB function in tumorigenesis. In addition, HMGB1 is a critical regulator of autophagy. Loss of HMGB1 inhibits autophagy and increases apoptosis. Suppression of autophagy promotes tumorigenesis and increases the effectiveness of anticancer therapy.

Figure 3. HMGB1 release and redox activity

HMGB1 can be passively released or actively secreted from the indicated immune and cancer cells under stress. The activity of HMGB1 varies with the redox states of the cysteine residues (C23, C45 and C106). All- reduced-HMGB1 has sole chemokine activity, whereas disulfide-HMGB1 has only cytokine activity, and all-oxidized-HMGB1 has neither.

Figure 4. Mechanism of HMGB1 release

(A) Endogenous and exogenous immune activators can produce secondary messenger molecules that will induce post-translational modifications (PTMs) of HMGB1 and subsequently CRM1-mediated HMGB1 nuclear export. Finally, HMGB1 is secreted by non-classical, lysosome-mediated exocytosis. “Ac” = acetylation, “Ar” = ADP-ribosylation, “Me” = methylation, “P” = phosphorylation, “Ox” = oxidation. (B) In pyroptosis, PAMPs and DAMPs promote the autophosphorylation and activation of PKR. Active PKR physically interacts with inflammasome and promotes the release of HMGB1 in a caspase 1-dependent way. (C) In apoptosis, chemotherapy and radiation promote activation of caspase-3 and caspase-7, which impair the mitochondrial respiratory chain, induce production of ROS, and result in HMGB1 release. (D) In necrosis, DNA damage activates PARP-1, which leads to ATP depletion, mitochondrial ROS production, and subsequent HMGB1 release. (E) In autophagy, starvation promotes ROS production, which leads to HMGB1 release in an ATG5-dependent way.

Figure 5. The HMGB1-mediated autophagy pathway

(A) The dual roles of autophagy in cancer. The main process of autophagy includes formation and maturation of the phagophore, autophagosome, and autolysosome, which lead to the degradation and recycling of the sequestered contents. During tumor development and in cancer therapy, autophagy promotes both tumor suppression and tumor survival. (B) Multiple roles of HMGB1 in autophagy. Nuclear HMGB1 modulates the expression of heat shock protein β-1 (HSPB1). Loss of either HMGB1 or HSPB1 results in a phenotypically similar deficiency in mitophagy and autophagy. This pathway requires phosphorylation of HSPB1 (both Ser15 and Ser86) to modulate actin polymerization and reorganization. Cytoplasmic HMGB1 is a novel Beclin 1-binding protein active in autophagy. HMGB1 C23 and C45 is required for HMGB1 binding to Beclin 1. p53 and unc-51-like kinase 1 (ULK1) have opposing roles in regulation of the HMGB1- Beclin 1 complex formation in cancer cells. The ULK1 kinase is an essential component of the core autophagy machinery. Extracellular HMGB1 induces autophagy by receptor for advanced glycation end products (RAGE), and this role is dependent on HMGB1’s redox state.