Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression

Tan,Yifan; Wang,Lei; Du,Yang; Liu,Xiuheng; Chen,Zhiyuan; Weng,Xiaodong; Guo,Jia; Chen,Hui; Wang,Min; Wang,Xiao

doi:10.3892/ijo.2018.4577

Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression

Authors:
- Yifan Tan
- Lei Wang
- Yang Du
- Xiuheng Liu
- Zhiyuan Chen
- Xiaodong Weng
- Jia Guo
- Hui Chen
- Min Wang
- Xiao Wang
View Affiliations

Affiliations: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: September 27, 2018 https://doi.org/10.3892/ijo.2018.4577
Pages: 2503-2517
Copyright: © Tan 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

Prostate cancer (PCa) is a malignant tumor with a high incidence in males. Localized tumors can be treated via surgery or radiation; however, it remains difficult to prevent disease progression. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader protein that binds to acetylated lysine on histones and has been reported to serve critical roles in numerous types of cancers. In the present study, it was demonstrated that BRD4 expression levels were significantly increased in cancerous prostate tissue specimens and cells, which were associated with clinical stage and metastasis. In addition, the present study reported that inhibition of BRD4 via short hairpin RNA or JQ1 (a bromodomain inhibitor) decreased PCa cell proliferation, induced G0/G1 cell cycle arrest and apoptosis, mitigated cell invasion and migration in vitro, and impaired tumor growth in vivo. Mechanistically, BRD4 inhibition-induced suppression of cell cycle progression was associated with the upregulation of p21 and cyclin D1. c-Myc and B-cell lymphoma-2 (Bcl-2), important genes responsible for cell cycle regulation and anti-apoptotic functions, were downregulated in response to BRD4 inhibition. Furthermore, the present study revealed that c-Myc expression was negatively regulated by p21, and that the induction of p21 via BRD4 inhibition was mediated by forkhead box protein O1 (FOXO1), rather than p53. In summary, the results of the present study suggested that the aberrant expression of BRD4 in PCa may induce carcinogenesis. In addition, a mechanism by which BRD4 inhibition suppresses cell proliferation via the regulation of FOXO1-p21-Myc signaling was proposed in the present study, which may contribute to the development of novel therapeutic approaches in the management of PCa.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
3	Zhu X, Albertsen PC, Andriole GL, Roobol MJ, Schroder FH and Vickers AJ: Risk-based prostate cancer screening. Eur Urol. 61:652–661. 2012. View Article : Google Scholar
4	Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, Tannock I, Drake CG and de Bono JS: Prostate cancer. Lancet. 387:70–82. 2016. View Article : Google Scholar
5	Mullins JK, Feng Z, Trock BJ, Epstein JI, Walsh PC and Loeb S: The impact of anatomical radical retropubic prostatectomy on cancer control: The 30-year anniversary. J Urol. 188:2219–2224. 2012. View Article : Google Scholar : PubMed/NCBI
6	Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 367:203–213. 2012. View Article : Google Scholar : PubMed/NCBI
7	Jung M, Gelato KA, Fernandez-Montalvan A, Siegel S and Haendler B: Targeting BET bromodomains for cancer treatment. Epigenomics-Uk. 7:487–501. 2015. View Article : Google Scholar
8	Meloche J, Potus F, Vaillancourt M, Bourgeois A, Johnson I, Deschamps L, Chabot S, Ruffenach G, Henry S, Breuils-Bonnet S, et al: Bromodomain-Containing protein 4: The epigenetic origin of pulmonary arterial hypertension. Circ Res. 117:525–535. 2015. View Article : Google Scholar : PubMed/NCBI
9	Chen R, Yik JH, Lew QJ and Chao SH: Brd4 and HEXIM1: Multiple roles in P-TEFb regulation and cancer. Biomed Res Int. 2014:2328702014.PubMed/NCBI
10	Noguchi-Yachide T: BET bromodomain as a target of epigenetic therapy. Chem Pharm Bull (Tokyo). 64:540–547. 2016. View Article : Google Scholar
11	Wu X, Liu D, Gao X, Xie F, Tao D, Xiao X, Wang L, Jiang G and Zeng F: Inhibition of BRD4 suppresses cell proliferation and induces apoptosis in renal cell carcinoma. Cell Physiol Biochem. 41:1947–1956. 2017. View Article : Google Scholar : PubMed/NCBI
12	French C: NUT midline carcinoma. Nat Rev Cancer. 14:149–150. 2014. View Article : Google Scholar
13	Andrieu G, Tran AH, Strissel KJ and Denis GV: BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling. Cancer Res. 76:6555–6567. 2016. View Article : Google Scholar : PubMed/NCBI
14	Liao YF, Wu YB, Long X, Zhu SQ, Jin C, Xu JJ and Ding JY: High level of BRD4 promotes non-small cell lung cancer progression. Oncotarget. 7:9491–9500. 2016. View Article : Google Scholar : PubMed/NCBI
15	Ferri E, Petosa C and McKenna CE: Bromodomains: Structure, function and pharmacology of inhibition. Biochem Pharmacol. 106:1–18. 2016. View Article : Google Scholar
16	Filippakopoulos P and Knapp S: Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 13:337–356. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sahai V, Redig AJ, Collier KA, Eckerdt FD and Munshi HG: Targeting BET bromodomain proteins in solid tumors. Oncotarget. 7:53997–54009. 2016. View Article : Google Scholar : PubMed/NCBI
18	Li GQ, Guo WZ, Zhang Y, Seng JJ, Zhang HP, Ma XX, Zhang G, Li J, Yan B, Tang HW, et al: Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget. 7:2462–2474. 2016.
19	Togel L, Nightingale R, Chueh AC, Jayachandran A, Tran H, Phesse T, Wu R, Sieber OM, Arango D, Dhillon AS, et al: Dual targeting of bromodomain and extraterminal domain proteins, and WNT or MAPK signaling, inhibits c-MYC expression and proliferation of colorectal cancer cells. Mol Cancer Ther. 15:1217–1226. 2016. View Article : Google Scholar : PubMed/NCBI
20	Urbanucci A, Barfeld SJ, Kytola V, Itkonen HM, Coleman IM, Vodak D, Sjoblom L, Sheng X, Tolonen T, Minner S, et al: Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer. Cell Rep. 19:2045–2059. 2017. View Article : Google Scholar : PubMed/NCBI
21	Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, et al: Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 510:278–282. 2014. View Article : Google Scholar : PubMed/NCBI
22	Mohler JL, Armstrong AJ, Bahnson RR, D'Amico AV, Davis BJ, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz EM, et al: Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw. 14:19–30. 2016. View Article : Google Scholar : PubMed/NCBI
23	Li JH, Liu S, Zhou H, Qu LH and Yang JH: StarBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 42:D92–D97. 2014. View Article : Google Scholar
24	Yang JH, Li JH, Shao P, Zhou H, Chen YQ and Qu LH: StarBase: A database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res. 39:D202–D209. 2011. View Article : Google Scholar
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
26	Wu X, Liu D, Tao D, Xiang W, Xiao X, Wang M, Wang M, Luo L, Li G, Zeng YF, et al: BRD4 regulates EZH2 transcription through upregulation of C-MYC and represents a novel therapeutic target in bladder cancer. Mol Cancer Ther. 15:1029–1042. 2016. View Article : Google Scholar : PubMed/NCBI
27	Cheng Z, Gong Y, Ma Y, Lu K, Lu X, Pierce LA, Thompson RC, Muller S, Knapp S and Wang J: Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin Cancer Res. 19:1748–1759. 2013. View Article : Google Scholar : PubMed/NCBI
28	Lee DH, Qi J, Bradner JE, Said JW, Doan NB, Forscher C, Yang H and Koeffler HP: Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 136:2055–2064. 2015. View Article : Google Scholar
29	Kumar K, Raza SS, Knab LM, Chow CR, Kwok B, Bentrem DJ, Popovic R, Ebine K, Licht JD and Munshi HG: GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci Rep. 5:94892015. View Article : Google Scholar : PubMed/NCBI
30	Georgakilas AG, Martin OA and Bonner WM: P21: A two-faced genome guardian. Trends Mol Med. 23:310–319. 2017. View Article : Google Scholar : PubMed/NCBI
31	Yang Y, Blee AM, Wang D, An J, Pan Y, Yan Y, Ma T, He Y, Dugdale J, Hou X, et al: Loss of FOXO1 cooperates with TMPRSS2-ERG overexpression to promote prostate tumorigenesis and cell invasion. Cancer Res. 77:6524–6537. 2017. View Article : Google Scholar : PubMed/NCBI
32	Tinkum KL, White LS, Marpegan L, Herzog E, Piwnica-Worms D and Piwnica-Worms H: Forkhead box O1 (FOXO1) protein, but not p53, contributes to robust induction of p21 expression in fasted mice. J Biol Chem. 288:27999–28008. 2013. View Article : Google Scholar : PubMed/NCBI
33	Litwin MS and Tan HJ: The diagnosis and treatment of prostate cancer: A review. JAMA. 317:2532–2542. 2017. View Article : Google Scholar : PubMed/NCBI
34	Basch E, Loblaw DA, Oliver TK, Carducci M, Chen RC, Frame JN, Garrels K, Hotte S, Kattan MW, Raghavan D, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 32:3436–3448. 2014. View Article : Google Scholar : PubMed/NCBI
35	Ning YM, Brave M, Maher VE, Zhang L, Tang S, Sridhara -R, Kim G, Ibrahim A and Pazdur R: U.S. Food and drug administration approval summary: Enzalutamide for the treatment of patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Oncologist. 20:960–966. 2015. View Article : Google Scholar : PubMed/NCBI
36	Xiang T, Bai JY, She C, Yu DJ, Zhou XZ and Zhao TL: Bromodomain protein BRD4 promotes cell proliferation in skin squamous cell carcinoma. Cell Signal. 42:106–113. 2018. View Article : Google Scholar
37	Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, Chen T, Jin J, Pan W, Cai X, et al: USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene. 34:3957–3967. 2015. View Article : Google Scholar
38	Rebello RJ, Pearson RB, Hannan RD and Furic L: Therapeutic approaches targeting MYC-Driven prostate cancer. Genes (Basel). 8. pp. E712017, View Article : Google Scholar
39	Kelly PN, Grabow S, Delbridge AR, Strasser A and Adams JM: Endogenous Bcl-xL is essential for Myc-driven lymphoma-genesis in mice. Blood. 118:6380–6386. 2011. View Article : Google Scholar : PubMed/NCBI
40	Gao X, Wu X, Zhang X, Hua W and Zhang Y, Maimaiti Y, Gao Z and Zhang Y: Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer. Biochem Biophys Res Commun. 469:679–685. 2016. View Article : Google Scholar
41	Karimian A, Ahmadi Y and Yousefi B: Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 42:63–71. 2016. View Article : Google Scholar
42	Hydbring P, Malumbres M and Sicinski P: Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol. 17:280–292. 2016. View Article : Google Scholar : PubMed/NCBI
43	Delbridge AR, Grabow S, Bouillet P, Adams JM and Strasser A: Functional antagonism between pro-apoptotic BIM and anti-apoptotic BCL-XL in MYC-induced lymphomagenesis. Oncogene. 34:1872–1876. 2015. View Article : Google Scholar
44	Pellicano F, Scott MT, Helgason GV, Hopcroft LE, Allan EK, Aspinall-O'Dea M, Copland M, Pierce A, Huntly BJ, Whetton AD, et al: The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. Stem Cells. 32:2324–2337. 2014. View Article : Google Scholar : PubMed/NCBI