title: An inhibitor of the acetyltransferases CBP/p300 exerts antineoplastic effects on gastrointestinal stromal tumor cells.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm featured by activated mutations of KIT and PDGFRA. Although overall survival rates have greatly improved by the development of receptor tyrosine kinase inhibitors, most patients ultimately acquire resistance due to secondary mutations of KIT or PDGFRA. Inhibition of the histone acetyltransferases (HATs) CREB‑binding protein (CBP) and p300 results in antineoplastic effects in various cancers. To determine whether CBP/p300 can serve as an antineoplastic target for GISTs, specific short interfering RNA sequences and the selective HAT inhibitor C646 were administered to GIST882 cells. Cell viability, apoptosis and the cell cycle were analysed using the Cell Counting Kit-8, a caspase-3/7 activity assay or Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and PI staining. Gene and protein expression levels were measured by quantitative real-time polymerase chain reaction and western blotting, respectively. Transcriptional blockage of CBP, rather than p300, resulted in suppression of cell proliferation. Interestingly, both CBP and p300 depletion enhanced caspase-3/7 activity. A lack of CBP and p300 caused ETS translocation variant 1 (ETV1) downregulation and KIT inhibition in GIST cells. Nevertheless, the absence of CBP, not p300, leads to extracellular signal-regulated kinase 1/2 inactivation and c-Jun NH2-terminal kinase activation, suggesting a more crucial role for CBP than p300 in cell proliferation and survival. Furthermore, proliferation of GIST cells was reduced by administration of C646, a selective HAT inhibitor for CBP/p300. Apoptosis induction and cell cycle arrest were detected after exposure to C646, indicating that its antitumor activities were supported by its antiproliferative and proapoptotic effects. Additionally, C646 treatment attenuated ETV1 protein expression and inactivated KIT-dependent pathways. Taken together, the present study suggests that CBP/p300 may serve as novel antineoplastic targets and that use of the selective HAT inhibitor C646 is a promising antitumor strategy for GISTs.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Meng-Li
authors.initials: ML
authors.lastname: Gu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Ya-Mei
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Hang-Ping
authors.initials: HP
authors.lastname: Yao
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Zun
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ji
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009578:Nitrobenzenes; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage*; D047069:Pyrazolones; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000099224:p300-CBP-Associated Factor
chemical_list: D001565:Benzoates; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D009578:Nitrobenzenes; D019009:Proto-Oncogene Proteins c-kit; D011720:Pyrazoles; D047069:Pyrazolones; D020797:Receptor, Platelet-Derived Growth Factor beta; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; C095239:ETV1 protein, human; C000605860:PDGFRB protein, human