HMGB1 promotes the development of castration‑resistant prostate cancer by regulating androgen receptor activation

Chen,Junyu; Xu,Duo; Wang,Taiwei; Yang,Zhaoyun; Yang,Yanrong; He,Kang; Zhao,Lijing

doi:10.3892/or.2022.8412

HMGB1 promotes the development of castration‑resistant prostate cancer by regulating androgen receptor activation

Authors:
- Junyu Chen
- Duo Xu
- Taiwei Wang
- Zhaoyun Yang
- Yanrong Yang
- Kang He
- Lijing Zhao
View Affiliations

Affiliations: Department of Rehabilitation, School of Nursing, Jilin University, Changchun, Jilin 130021, P.R. China, School of Medicine, Tongji University, Shanghai 200092, P.R. China
Published online on: September 19, 2022 https://doi.org/10.3892/or.2022.8412
Article Number: 197
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

AR signalling pathway reactivation plays a key role in the development of castration‑resistant prostate cancer (CRPC). High‑mobility group protein B1 (HMGB1) is an important factor involved in the occurrence and development of a variety of tumours by regulating gene transcription. In the present study, the association between HMGB1 and prostate cancer (PCa) and the effects of HMGB1 on androgen receptor (AR) transcription and signalling pathway reactivation in PCa cells in vitro and in vivo were evaluated. A bioinformatics method was used to determine the mRNA expression level of HMGB1 in PCa specimens and its correlation with the mRNA expression of AR. Immunohistochemical staining was used to detect the expression of these proteins in clinical PCa samples. Reporter gene and ChIP assays were performed to determine the activity of AR and the effect of HMGB1 on the ability of AR to bind to the promoters of prostate specific antigen and transmembrane protease, serine 2. A bioluminescence resonance energy transfer assay was employed to observe the direct interaction between HMGB1 and AR protein. Additionally, a castrated nude mouse xenograft tumour model was established to verify the effect of HMGB1 on PCa. The results revealed that HMGB1 expression was significantly increased in PCa specimens, which may have a strong correlation with AR expression. Moreover, HMGB1 could reactivate the AR signalling pathway, directly interact with AR, and promote the development of CRPC in an androgen‑independent manner. The results of the present study indicated that HMGB1 promoted the development of CRPC by interacting with AR, which inferred that decreasing the expression of HMGB1 may be a potential effective method for CRPC prevention and treatment.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Glina S, Rivero MA, Morales A and Morgentaler A: Studies on prostatic cancer I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate by Charles Huggins and Clarence V. Hodges. J Sex Med. 7:640–644. 2010. View Article : Google Scholar : PubMed/NCBI
3	Guan W, Li F, Zhao Z, Zhang Z, Hu J and Zhang Y: Tumor-associated macrophage promotes the survival of cancer cells upon docetaxel chemotherapy via the CSF1/CSF1R-CXCL12/CXCR4 axis in castration-resistant prostate cancer. Genes (Basel). 12:7732021. View Article : Google Scholar : PubMed/NCBI
4	Kluetz PG, Ning YM, Maher VE, Zhang L, Tang S, Ghosh D, Aziz R, Palmby T, Pfuma E, Zirkelbach JF, et al: Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and drug administration drug approval summary. Clin Cancer Res. 19:6650–6656. 2013. View Article : Google Scholar : PubMed/NCBI
5	Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 367:1187–1197. 2012. View Article : Google Scholar : PubMed/NCBI
6	Egan A, Dong Y, Zhang H, Qi Y, Balk SP and Sartor O: Castration-resistant prostate cancer: Adaptive responses in the androgen axis. Cancer Treat Rev. 40:426–433. 2014. View Article : Google Scholar : PubMed/NCBI
7	van Royen ME, van Cappellen WA, de Vos C, Houtsmuller AB and Trapman J: Stepwise androgen receptor dimerization. J Cell Sci. 125:1970–1979. 2012.PubMed/NCBI
8	Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 324:787–790. 2009. View Article : Google Scholar : PubMed/NCBI
9	Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, et al: Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 16:152–160. 2015. View Article : Google Scholar : PubMed/NCBI
10	Xu D, Zhan Y, Qi Y, Cao B, Bai S, Xu W, Gambhir SS, Lee P, Sartor O, Flemington EK, et al: Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res. 75:3663–3671. 2015. View Article : Google Scholar : PubMed/NCBI
11	Xue J, Suarez JS, Minaai M, Li S, Gaudino G, Pass HI, Carbone M and Yang H: HMGB1 as a therapeutic target in disease. J Cell Physiol. 236:3406–3419. 2021. View Article : Google Scholar : PubMed/NCBI
12	Jung AR, Kim GE, Kim MY, Ha US, Hong SH, Lee JY, Kim SW and Park YH: HMGB1 promotes tumor progression and invasion through HMGB1/TNFR1/NF-κB axis in castration-resistant prostate cancer. Am J Cancer Res. 11:2215–2227. 2021.PubMed/NCBI
13	Chou YE, Yang PJ, Lin CY, Chen YY, Chiang WL, Lin PX, Huang ZY, Huang M, Ho YC and Yang SF: The impact of HMGB1 polymorphisms on prostate cancer progression and clinicopathological characteristics. Int J Environ Res Public Health. 17:72472020. View Article : Google Scholar : PubMed/NCBI
14	Das D, Peterson RC and Scovell WM: High mobility group B proteins facilitate strong estrogen receptor binding to classical and half-site estrogen response elements and relax binding selectivity. Mol Endocrinol. 18:2616–2632. 2004. View Article : Google Scholar : PubMed/NCBI
15	Powell E and Xu W: Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers. Proc Natl Acad Sci USA. 105:19012–19017. 2008. View Article : Google Scholar : PubMed/NCBI
16	Bjerregaard-Olesen C, Ghisari M, Kjeldsen LS, Wielsøe M and Bonefeld-Jørgensen EC: Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor. Steroids. 105:50–58. 2016. View Article : Google Scholar : PubMed/NCBI
17	Mafuvadze B, Liang YY and Hyder SM: Cholesterol synthesis inhibitor RO 48-8071 suppresses transcriptional activity of human estrogen and androgen receptor. Oncol Rep. 32:1727–1733. 2014. View Article : Google Scholar : PubMed/NCBI
18	Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, Kalyana-Sundaram S, Wei JT, Rubin MA, Pienta KJ, et al: Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 39:41–51. 2007. View Article : Google Scholar : PubMed/NCBI
19	Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, et al: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 1:203–209. 2002. View Article : Google Scholar : PubMed/NCBI
20	Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L, McDonald C, Thomas R, Dhir R, Finkelstein S, et al: Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol. 22:2790–2799. 2004. View Article : Google Scholar : PubMed/NCBI
21	Vanaja DK, Cheville JC, Iturria SJ and Young CY: Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63:3877–3882. 2003.PubMed/NCBI
22	Tian Y, Zhao L, Zhang H, Liu X, Zhao L, Zhao X, Li Y and Li J: AKR1C3 overexpression may serve as a promising biomarker for prostate cancer progression. Diagn Pathol. 9:422014. View Article : Google Scholar : PubMed/NCBI
23	Chen J, Xia Y, Peng Y, Wu S, Liu W, Zhang H, Wang T, Yang Z, Zhao S and Zhao L: Analysis of the association between KIN17 expression and the clinical features/prognosis of epithelial ovarian cancer, and the effects of KIN17 in SKOV3 cells. Oncol Lett. 21:4752021. View Article : Google Scholar : PubMed/NCBI
24	Yang Y, Liu T, Hu C, Xia H, Liu W, Chen J, Wu S, Jiang Y, Xu Y, Liu W and Zhao L: Ferroptosis inducer erastin downregulates androgen receptor and its splice variants in castration-resistant prostate cancer. Oncol Rep. 45:252021. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Chen J, Zhao S, Tan W, Wang T, Wu S, Wang C, Jiang Y, Zhou T, Zhang Z and Zhao L: Attenuated Salmonella carrying plasmid co-expressing HPV16 L1 and siRNA-E6 for cervical cancer therapy. Sci Rep. 11:200832021. View Article : Google Scholar : PubMed/NCBI
27	Li T, Gui Y, Yuan T, Liao G, Bian C, Jiang Q, Huang S, Liu B and Wu D: Overexpression of high mobility group box 1 with poor prognosis in patients after radical prostatectomy. BJU Int. 110:E1125–E1130. 2012. View Article : Google Scholar : PubMed/NCBI
28	Wang C, Peng G, Huang H, Liu F, Kong DP, Dong KQ, Dai LH, Zhou Z, Wang KJ, Yang J, et al: Blocking the feedback loop between neuroendocrine differentiation and macrophages improves the therapeutic effects of enzalutamide (MDV3100) on prostate cancer. Clin Cancer Res. 24:708–723. 2018. View Article : Google Scholar : PubMed/NCBI
29	Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y and Muramatsu M: The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem Biophys Res Commun. 243:122–126. 1998. View Article : Google Scholar : PubMed/NCBI
30	Cao B, Qi Y, Zhang G, Xu D, Zhan Y, Alvarez X, Guo Z, Fu X, Plymate SR, Sartor O, et al: Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget. 5:1646–1656. 2014. View Article : Google Scholar : PubMed/NCBI
31	Dong Y, Lee SO, Zhang H, Marshall J, Gao AC and Ip C: Prostate specific antigen expression is down-regulated by selenium through disruption of androgen receptor signaling. Cancer Res. 64:19–22. 2004. View Article : Google Scholar : PubMed/NCBI
32	Collak FK, Demir U and Sagir F: YAP1 is involved in tumorigenic properties of prostate cancer cells. Pathol Oncol Res. 26:867–876. 2020. View Article : Google Scholar : PubMed/NCBI