Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers

Abstract

The high mobility group box 1 (HMGB1) protein, a non-histone nuclear factor, is overexpressed and localizes to the cytoplasm in some cancer cells. However, the mechanism of cytoplasmic HMGB1 transport, extracellular secretion, and its role in cancer progression is not clear. To simulate the activated state of HMGB1, we mutated serine residues of nuclear localization signals (NLSs) to glutamic acid and performed transfection assays. We carried out a kinase inhibitor study and evaluated the cell migration by invasion assay. We showed that phosphorylated HMGB1 localizes in the cytoplasm of colon cancer cells and also showed the interaction of PKC and HMGB1 by immunoprecipitation analysis. Concurrent mutations at six serine residues (35, 39, 42, 46, 53, and 181) to glutamic acid induced the nuclear to cytoplasmic transport of HMGB1, which was detected in the culture medium. We also observed that the secretion of HMGB1 correlated with increased cancer cell invasiveness. Our results suggest that phosphorylated HMGB1 is transported to the cytoplasm, is subsequently secreted from the cell, and has a role in tumor progression through the activation of genes related to cell migration.

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

“…And it is safe to say that post translational modifications play an important role in the nucleocytoplasmic redistribution. As mentioned above, oxidation, hyperacetylation and phosphorylation of HMGB1 contribute to its cytoplasmic relocation in inflammatory and cancer cells (Hoppe et al, 2006;Youn et al, 2006;Tsung et al, 2007;Kang et al, 2009;Evankovich et al, 2010;Lee et al, 2012). Experiments in Schistosoma mansoni conclusively demonstrated that acetylation and phosphorylation played roles in cellular trafficking, culminating with its secretion to the extracellular milieu de Abreu da Silva et al, 2011).…”

“…Later, it has been demonstrated that decreased histone deacetylases(HDACs) activity in hepatocytes, following ischemia and reperfusion, was a mechanism that promoted hyperacetylation and secretion of HMGB1 (Evankovich et al, 2010). In addition, several investigations demonstrated that HMGB1with phosphorylation at specific serine residues of nuclear localization signals (NLS) regions was transported to cytoplasm, and subsequently secreted from cells (Youn et al, 2006;Kang et al, 2009;Lee et al, 2012). Hence, it is safe to say that post translational modifications (PTMs) play a critical role in governing the nucleocytoplasmic shuttling of HMGB1.…”

Expression of high mobility group box 1 protein predicts a poorer prognosis for patients with osteosarcoma

“…HMGB1 is a nuclear protein that acts as a chromatin-binding factor and exists in the nuclei of cancerous and normal cells (17). HMGB1 modifies the interaction of DNA with transcription factors, including p53 steroid hormone receptors, by non-specifically binding to the minor groove of DNA, thereby playing a role in DNA repair, transcription, differentiation, extracellular signalization, and somatic recombination (39).…”

“…HMGB1 demonstrates affinity for various DNA structures, including supercoiled and single-stranded DNA, B-and Z-DNA, DNA mini-circles, 4-way junctions, looped structures, hemicatenated DNA, and triplex DNA (39). Native HMGB1 released from tumor cells inhibits DNA replication.…”

A New Therapeutic Target for Treatment of Cancer: High Mobility Group Box 1 Protein

“…DNA'nın küçük oluğuna nonspesifik şekilde bağlanarak p53, steroid hormon reseptörleri de dahil olmak üzere bazı transkripsiyon faktörleri-nin DNA ile etkileşimini modifiye eder. DNA onarımında, transkripsiyonda, diferansiasyonda, extraselüler sinyalizasyonda, somatik rekombinasyonda rol oynar [2]. Bu nükleer fonksiyonları-nın yanı sıra nekroze hücrelerden pasif, inflamasyonda rol oynayan hücrelerden aktif sekrete edilerek ekstraselüler sinyal molekülü olarak da fonksiyon görür.…”