title: BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Because bromodomain (BRD) and extra terminal domain (BET) proteins are "readers" of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18, and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18, and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer.
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sahai
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and Jesse Brown VA Medical Center; and.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Surgical Oncology, Feinberg School of Medicine, Northwestern University;
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Knab
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Chow
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and.
authors.forename: Sania S
authors.initials: SS
authors.lastname: Raza
authors.affiliation: Surgical Oncology, Feinberg School of Medicine, Northwestern University; Jesse Brown VA Medical Center; and The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ebine
authors.affiliation: Authors' Affiliations: Divisions of Hematology/Oncology and Jesse Brown VA Medical Center; and The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois h-munshi@northwestern.edu.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins; D003094:Collagen; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D003094:Collagen; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C109570:BRDT protein, human