HMGB1 Promotes Prostate Cancer Development and Metastasis by Interacting with Brahma-Related Gene 1 and Activating the Akt Signaling Pathway

Abstract

<b>Background and Aim</b>: We have previously shown that high-mobility group box 1 (<i>HMGB1</i>) is an independent biomarker for shortened survival of prostate cancer (PCa) patients. However, the specific role of <i>HMGB1</i> in tumor development and progression remains largely unknown. In this study, we investigated the molecular mechanisms of <i>HMGB1</i> in PCa tumorigenesis. <b>Methods</b>: Gain-of-function and loss-of-function experiments were used to determine the biological functions of <i>HMGB1</i> both <i>in vitro</i> and <i>in vivo</i>. Bioinformatic analysis, immunoprecipitation, and immunofluorescence assays were applied to discern and examine the relationship between <i>HMGB1</i> and its potential targets. Specimens from 64 patients with PCa were analyzed for the expression of <i>HMGB1</i> and its relationship with Brahma-related gene 1 (<i>BRG1</i>) was examined by immunohistochemistry. <b>Results</b>: The results demonstrated that ectopic expression of <i>HMGB1</i> facilitated growth and metastasis of PCa by enhancing <i>Akt</i> signaling pathway and promoting epithelial-mesenchymal transition (EMT), while silencing of <i>HMGB1</i> showed the opposite effects. Mechanistically, <i>HMGB1</i> exerted these functions through its interaction with <i>BRG1</i> which may augment <i>BRG1</i> function and activate the <i>Akt</i> signaling pathway thereby promoting EMT. Importantly, both <i>HMGB1</i> and <i>BRG1</i> expression was markedly increased in human PCa tissues. <b>Conclusions</b>: Taken together, these findings indicate that upregulation of <i>HMGB1</i> promotes PCa development <i>via</i> activation of <i>Akt</i> and accelerates metastasis through regulating <i>BRG1</i>-mediated EMT. <i>HMGB1</i> could be used as a novel potential target for the treatment of PCa.