Abstract
Here we provide evidence that RBBP4 modulates temozolomide (TMZ) sensitivity through coordinate regulation of two key DNA repair genes critical for recovery from TMZ-induced DNA damage: methylguanine-DNA-methyltransferase (MGMT) and RAD51. Disruption of RBBP4 enhanced TMZ sensitivity, induced synthetic lethality to PARP inhibition, and increased DNA damage signaling in response to TMZ. Moreover, RBBP4 silencing enhanced TMZ-induced H2AX phosphorylation and apoptosis in GBM cells. Intriguingly, RBBP4 knockdown suppressed the expression of MGMT, RAD51, and other genes in association with decreased promoter H3K9 acetylation (H3K9Ac) and increased H3K9 tri-methylation (H3K9me3). Consistent with these data, RBBP4 interacts with CBP/p300 to form a chromatin-modifying complex that binds within the promoter of MGMT, RAD51, and perhaps other genes. Globally, RBBP4 positively and negatively regulates genes involved in critical cellular functions including tumorigenesis. The RBBP4/CBP/p300 complex may provide an interesting target for developing therapy-sensitizing strategies for GBM and other tumors.
Keywords:
MGMT; RBBP4; glioblastoma; resistance; temozolomide.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Antineoplastic Agents, Alkylating / pharmacology
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Apoptosis / drug effects
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Damage / drug effects
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Dacarbazine / analogs & derivatives*
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Dacarbazine / pharmacology
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E1A-Associated p300 Protein / genetics
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E1A-Associated p300 Protein / metabolism
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Histones / metabolism
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Humans
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Microscopy, Fluorescence
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Phosphorylation / drug effects
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering / metabolism
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Rad51 Recombinase / genetics
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Rad51 Recombinase / metabolism
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Real-Time Polymerase Chain Reaction
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Retinoblastoma-Binding Protein 4 / antagonists & inhibitors
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Retinoblastoma-Binding Protein 4 / genetics
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Retinoblastoma-Binding Protein 4 / metabolism*
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Temozolomide
Substances
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Antineoplastic Agents, Alkylating
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Histones
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RNA, Small Interfering
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Retinoblastoma-Binding Protein 4
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Dacarbazine
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DNA (Cytosine-5-)-Methyltransferases
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E1A-Associated p300 Protein
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EP300 protein, human
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RAD51 protein, human
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Rad51 Recombinase
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Temozolomide