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

doi:10.1016/j.celrep.2016.02.045

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

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28 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 language	English (US)
Pages (from-to)	2587-2598
Number of pages	12
Journal	Cell reports
Volume	14
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2016.02.045
State	Published - Mar 22 2016

Keywords

Glioblastoma
MGMT
RBBP4
Resistance
Temozolomide

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2016.02.045

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Kitange, G. J., Mladek, A. C., Schroeder, M. A., Pokorny, J. C., Carlson, B. L., Zhang, Y., Nair, A. A., Lee, J. H., Yan, H., Decker, P. A., Zhang, Z., & Sarkaria, J. N. (2016). Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins. Cell reports, 14(11), 2587-2598. https://doi.org/10.1016/j.celrep.2016.02.045

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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.",

keywords = "Glioblastoma, MGMT, RBBP4, Resistance, Temozolomide",

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

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doi = "10.1016/j.celrep.2016.02.045",

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T1 - Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins

AU - Kitange, Gaspar J.

AU - Mladek, Ann C.

AU - Schroeder, Mark A.

AU - Pokorny, Jenny C.

AU - Carlson, Brett L.

AU - Zhang, Yuji

AU - Nair, Asha A.

AU - Lee, Jeong Heon

AU - Yan, Huihuang

AU - Decker, Paul A.

AU - Zhang, Zhiguo

AU - Sarkaria, Jann N.

PY - 2016/3/22

Y1 - 2016/3/22

N2 - 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.

AB - 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.

KW - Glioblastoma

KW - MGMT

KW - RBBP4

KW - Resistance

KW - Temozolomide

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ER -

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

Abstract

Keywords

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