title: BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance.
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.
authors: Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China.
authors: Yong-Hui
authors: YH
authors: Wang
authors: Emergency Department of Weifang Traditional Chinese Hospital, Weifang, Shandong, P.R. China.
authors: Ya-Na
authors: YN
authors: Sui
authors: Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China.
authors: Kai
authors: K
authors: Yan
authors: Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China.
authors: Li-Shan
authors: LS
authors: Wang
authors: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, P.R. China.
authors: Fei
authors: F
authors: Wang
authors: Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, P.R. China.
authors: Jia-Hua
authors: JH
authors: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000093542:Gemcitabine; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C509239:SHH protein, human