RBBP4-p300 axis modulates expression of genes essential for cell survival and is a potential target for therapy in glioblastoma.

Autor:	Mladek AC; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Yan H; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA., Tian S; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA., Decker PA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA., Burgenske DM; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Bakken K; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Hu Z; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., He L; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Connors MA; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Carlson BL; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Wilson J; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA., Bommi-Reddy A; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA., Conery A; Constellation Pharmaceuticals, Cambridge, Massachusetts, USA., Eckel-Passow JE; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA., Sarkaria JN; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Kitange GJ; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2022 Aug 01; Vol. 24 (8), pp. 1261-1272.
DOI:	10.1093/neuonc/noac051
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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