title: Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins.
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.
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: kitange.gaspar@mayo.edu.
authors.forename: Gaspar J
authors.initials: GJ
authors.lastname: Kitange
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Mladek
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Pokorny
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Carlson
authors.affiliation: Department of Biostatistics and Bioinformatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics and Bioinformatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biostatistics and Bioinformatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Huihuang
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Biostatistics and Bioinformatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
mesh_terms: D000107:Acetylation / Q000187:drug effects; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D056505:Retinoblastoma-Binding Protein 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006657:Histones; D034741:RNA, Small Interfering; D056505:Retinoblastoma-Binding Protein 4; D003606:Dacarbazine; D004248:DNA (Cytosine-5-)-Methyltransferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000077204:Temozolomide
keywords: MGMT; RBBP4; glioblastoma; resistance; temozolomide