Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins

Autor: Jeong Heon Lee, Mark A. Schroeder, Zhiguo Zhang, Huihuang Yan, Jann N. Sarkaria, Yuji Zhang, Gaspar J. Kitange, Brett L. Carlson, Asha Nair, Ann C. Mladek, Jenny C. Pokorny, Paul A. Decker
Rok vydání: 2016
Předmět:
0301 basic medicine
Chromatin Immunoprecipitation
DNA repair
DNA damage
Poly ADP ribose polymerase
Apoptosis
Synthetic lethality
Real-Time Polymerase Chain Reaction
medicine.disease_cause
Article
General Biochemistry
Genetics and Molecular Biology
resistance
Histones
03 medical and health sciences
Cell Line
Tumor
Temozolomide
medicine
Humans
Gene silencing
DNA (Cytosine-5-)-Methyltransferases
Phosphorylation
RNA
Small Interfering
Promoter Regions
Genetic
lcsh:QH301-705.5
neoplasms
RBBP4
Antineoplastic Agents
Alkylating
Gene knockdown
biology
Acetylation
nervous system diseases
Dacarbazine
030104 developmental biology
Histone
lcsh:Biology (General)
Microscopy
Fluorescence
biology.protein
Cancer research
RNA Interference
Rad51 Recombinase
Retinoblastoma-Binding Protein 4
MGMT
Glioblastoma
Carcinogenesis
E1A-Associated p300 Protein
DNA Damage
Zdroj: Cell Reports, Vol 14, Iss 11, Pp 2587-2598 (2016)
ISSN: 2211-1247
Popis: SummaryHere 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.
Databáze: OpenAIRE
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