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Neuro Oncol ; 24(8): 1261-1272, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35231103

ABSTRACT

BACKGROUND: RBBP4 activates transcription by histone acetylation, but the partner histone acetyltransferases are unknown. Thus, we investigated the hypothesis that RBBP4 interacts with p300 in a complex in glioblastoma (GBM). METHODS: shRNA silencing of RBBP4 or p300 and RNAseq was used to identify genes co-regulated by RBBP4 and p300 in GBM43 patient-derived xenograft (PDX). RBBP4/p300 complex was demonstrated using proximity ligation assay (PLA) and ChIPseq delineated histone H3 acetylation and RBBP4/p300 complex binding in promoters/enhancers. Temozolomide (TMZ)-induced DNA double strand breaks (DSBs) were evaluated by γ-H2AX and proliferation by CyQuant and live cell monitoring assays. In vivo efficacy was based on survival of mice with orthotopic tumors. RESULTS: shRBBP4 and shp300 downregulated 4768 genes among which 1485 (31%) were commonly downregulated by both shRNAs, while upregulated genes were 2484, including 863 (35%) common genes. The pro-survival genes were the top-ranked among the downregulated genes, including C-MYC. RBBP4/p300 complex was demonstrated in the nucleus, and shRBBP4 or shp300 significantly sensitized GBM cells to TMZ compared to the control shNT in vitro (P < .05). Moreover, TMZ significantly prolonged the survival of mice bearing GBM22-shRBBP4 orthotopic tumors compared with control shNT tumors (median shNT survival 52 days vs. median shRBBP4 319 days; P = .001). CREB-binding protein (CBP)/p300 inhibitor CPI-1612 suppressed H3K27Ac and RBBP4/p300 complex target proteins, including C-MYC, and synergistically sensitized TMZ in vitro. Pharmacodynamic evaluation confirmed brain penetration by CPI-1612 supporting further investigation to evaluate efficacy to sensitize TMZ. CONCLUSIONS: RBBP4/p300 complex is present in GBM cells and is a potential therapeutic target.


Subject(s)
Brain Neoplasms , E1A-Associated p300 Protein , Glioblastoma , Retinoblastoma-Binding Protein 4 , Acetylation , Animals , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Survival , Drug Resistance, Neoplasm , E1A-Associated p300 Protein/genetics , E1A-Associated p300 Protein/metabolism , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Mice , Promoter Regions, Genetic , Retinoblastoma-Binding Protein 4/genetics , Retinoblastoma-Binding Protein 4/metabolism , Temozolomide/pharmacology , Temozolomide/therapeutic use , Xenograft Model Antitumor Assays
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