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

Abstract

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

Upregulated circZMIZ1 promotes the proliferation of prostate cancer cells and is a valuable marker in plasma

“…Cell cycle analysis. Cell cycle analysis was executed as described previously [19,20]. Briefly, we collected the transfected cells by centrifugation (500×g, 5 min).…”

Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells

“…In addition, extracellular HMGB1, after either active release from cells or passive release upon lytic cell death, functions as a pro-inflammatory cytokine and perpetuates inflammatory responses in a wide variety of pathologies [11]. Owing to its versatile role in cancer, HMGB1 has been proposed as a potential cancer biomarker of survival and a target for cancer therapy [12]. Although the role of HMGB1 in tumorigenesis, progression, invasion, metastasis, and prognosis in different malignancies has been…”

The Impact of HMGB1 Polymorphisms on Prostate Cancer Progression and Clinicopathological Characteristics

“…Prostate cancer is the second most common cause of male malignancy worldwide [ 1 , 2 ]. In Taiwan, it is the fifth most common cancer, with the seventh-highest cancer-related mortality rate [ 3 ].…”

“…High-mobility group box 1 ( HMGB1 ) is a member of the HMG1-type polypeptides and acts as a DNA chaperone, sustaining nucleosome dynamics and chromosomal stability [ 1 , 12 , 13 ]. In prostate cancer, it was found that targeting HMGB1 with short hairpin RNA (shRNA) in prostate cancer cells leads to an inhibition of prostate cancer cell survival [ 14 ].…”

“…Overexpression of HMGB1 was observed to be significantly associated with poor biochemical recurrence (BCR)-free survival in patients after radical prostatectomy [ 15 ]. Moreover, HMGB1 was suggested as a novel target for potential therapeutics since highly expressed HMGB1 was found to be associated with the epithelial-to-mesenchymal transition (EMT) and the overexpression of MMP-1, MMP-3, and MMP-10 via the RAGE/NF-κB signaling pathways, facilitating prostate cancer metastasis [ 1 , 16 , 17 , 18 , 19 , 20 ]. Furthermore, polymorphisms of HMGB1 have been associated with many cancers, including oral squamous cell carcinoma (OSCC) [ 21 , 22 ], lung cancer [ 23 , 24 , 25 , 26 ], breast cancer [ 27 , 28 , 29 ], gastric cancer [ 30 ], hepatocellular carcinoma (HCC) [ 31 , 32 ], and colorectal cancer (CRC) [ 33 ], and it was suggested that the SNPs of HMGB1 may provide a potential biomarker for predicting cancer risk, tumor development, or chemotherapy responses [ 21 , 25 , 27 , 31 ].…”