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

Gaspar J. Kitange, Ann C. Mladek, Mark A. Schroeder, Jenny C. Pokorny, Brett L. Carlson, Yuji Zhang, Asha A. Nair, Jeong Heon Lee, Huihuang Yan, Paul A. Decker, Zhiguo Zhang, Jann N. Sarkaria

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2587-2598
Number of pages12
JournalCell reports
Volume14
Issue number11
DOIs
StatePublished - Mar 22 2016

Keywords

  • Glioblastoma
  • MGMT
  • RBBP4
  • Resistance
  • Temozolomide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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