BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance

Wang,Yong-Hui; Sui,Ya-Na; Yan,Kai; Wang,Li-Shan; Wang,Fei; Zhou,Jia-Hua

doi:10.3892/or.2015.3774

BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance

Authors:
- Yong-Hui Wang
- Ya-Na Sui
- Kai Yan
- Li-Shan Wang
- Fei Wang
- Jia-Hua Zhou
View Affiliations

Affiliations: Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China, Emergency Department of Weifang Traditional Chinese Hospital, Weifang, Shandong, P.R. China, Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, P.R. China
Published online on: January 30, 2015 https://doi.org/10.3892/or.2015.3774
Pages: 1699-1706

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

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive carcinoma with a poor prognosis. To date, there is no effective treatment for this fatal disease. The manipulation of epigenetic proteins, such as BRD4, has recently emerged as an alternative therapeutic strategy. Our objective was to analyze the effect of BRD4 on the cell progression and chemoresistance of PDAC and the novel mechanisms involved. In the present study, we firstly revealed that the expression of BRD4 was significantly upregulated in PDAC cell lines, compared to that in human pancreatic duct epithelial cells. An in vitro assay showed that the suppression of BRD4 impaired PDAC cell viability and proliferation. Similarly, the tumor growth rate was also decreased in vivo after silencing of BRD4. Furthermore, we showed that the expression of BRD4 was increased after treatment with gemcitabine (GEM). Combination treatment of GEM and BRD4 silencing had a synergistic effect on the chemotherapeutic efficacy in the PANC-1 and MIAPaCa-2 cell lines, and significantly promoted apoptosis. In particular, we demonstrated that BRD4 activated the Sonic hedgehog (Shh) signaling pathway members in a ligand-independent manner in the PDAC cells. Together, our results indicate the important role of BRD4 in PDAC cell proliferation and chemoresistance and suggests that BRD4 is a promising target directed against the transcriptional program of PDAC.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar : PubMed/NCBI
3	Davis JL, Pandalai PK, Ripley RT, Langan RC and Avital I: Expanding surgical treatment of pancreatic cancer: the role of regional chemotherapy. Pancreas. 41:678–684. 2012. View Article : Google Scholar : PubMed/NCBI
4	Yang Z, He N and Zhou Q: Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G₁ gene expression and cell cycle progression. Mol Cell Biol. 28:967–976. 2008. View Article : Google Scholar :
5	Nicodeme E, Jeffrey KL, Schaefer U, et al: Suppression of inflammation by a synthetic histone mimic. Nature. 468:1119–1123. 2010. View Article : Google Scholar : PubMed/NCBI
6	Loven J, Hoke HA, Lin CY, et al: Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 153:320–334. 2013. View Article : Google Scholar : PubMed/NCBI
7	Chapuy B, McKeown MR, Lin CY, et al: Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 24:777–790. 2013. View Article : Google Scholar : PubMed/NCBI
8	Ott CJ, Kopp N, Bird L, et al: BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 120:2843–2852. 2012. View Article : Google Scholar : PubMed/NCBI
9	Pastori C, Daniel M, Penas C, et al: BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics. 9:611–620. 2014. View Article : Google Scholar : PubMed/NCBI
10	Lockwood WW, Zejnullahu K, Bradner JE and Varmus H: Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA. 109:19408–19413. 2012. View Article : Google Scholar : PubMed/NCBI
11	Sahai V, Kumar K, Knab LM, et al: BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen. Mol Cancer Ther. 13:1907–1917. 2014. View Article : Google Scholar : PubMed/NCBI
12	Berman DM, Karhadkar SS, Maitra A, et al: Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 425:846–851. 2003. View Article : Google Scholar : PubMed/NCBI
13	Thayer SP, di Magliano MP, Heiser PW, et al: Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 425:851–856. 2003. View Article : Google Scholar : PubMed/NCBI
14	Xu M, Li L, Liu Z, et al: ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance. Cancer Lett. 333:152–158. 2013. View Article : Google Scholar : PubMed/NCBI
15	Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, et al: BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 73:6264–6276. 2013. View Article : Google Scholar : PubMed/NCBI
16	Tang Y, Gholamin S, Schubert S, et al: Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 20:732–740. 2014. View Article : Google Scholar : PubMed/NCBI
17	Onishi H, Kai M, Odate S, et al: Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci. 102:1144–1150. 2011. View Article : Google Scholar : PubMed/NCBI
18	Nolan-Stevaux O, Lau J, Truitt ML, et al: GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 23:24–36. 2009. View Article : Google Scholar : PubMed/NCBI
19	Patel AJ, Liao CP, Chen Z, Liu C, Wang Y and Le LQ: BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep. 6:81–92. 2014. View Article : Google Scholar : PubMed/NCBI
20	Lamoureux F, Baud’huin M, Rodriguez Calleja L, et al: Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle. Nat Commun. 5:35112014. View Article : Google Scholar : PubMed/NCBI
21	Rodriguez RM, Huidobro C, Urdinguio RG, et al: Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer. J Mol Med. 90:587–595. 2012. View Article : Google Scholar
22	Crawford NP, Alsarraj J, Lukes L, et al: Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA. 105:6380–6385. 2008. View Article : Google Scholar : PubMed/NCBI
23	Mertz JA, Conery AR, Bryant BM, et al: Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA. 108:16669–16674. 2011. View Article : Google Scholar : PubMed/NCBI
24	Geissler K and Zach O: Pathways involved in Drosophila and human cancer development: the Notch, Hedgehog, Wingless, Runt, and Trithorax pathway. Ann Hematol. 91:645–669. 2012. View Article : Google Scholar : PubMed/NCBI
25	Teglund S and Toftgård R: Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 1805:181–208. 2010.PubMed/NCBI