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视网膜母细胞瘤结合蛋白4通过调节DNA修复蛋白来调控胶质母细胞瘤对替莫唑胺的敏感性。

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

作者信息

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

机构信息

Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.

出版信息

Cell Rep. 2016 Mar 22;14(11):2587-98. doi: 10.1016/j.celrep.2016.02.045. Epub 2016 Mar 10.

DOI:10.1016/j.celrep.2016.02.045
PMID:26972001
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4805508/
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.

摘要

我们在此提供证据表明，RBBP4通过对两个关键的DNA修复基因进行协同调控来调节替莫唑胺（TMZ）敏感性，这两个基因对从TMZ诱导的DNA损伤中恢复至关重要：甲基鸟嘌呤-DNA-甲基转移酶（MGMT）和RAD51。RBBP4的破坏增强了TMZ敏感性，诱导了对PARP抑制的合成致死性，并增加了对TMZ的DNA损伤信号传导。此外，RBBP4沉默增强了TMZ诱导的GBM细胞中H2AX磷酸化和凋亡。有趣的是，RBBP4敲低抑制了MGMT、RAD51和其他基因的表达，同时伴随着启动子H3K9乙酰化（H3K9Ac）降低和H3K9三甲基化（H3K9me3）增加。与这些数据一致，RBBP4与CBP/p300相互作用形成一种染色质修饰复合物，该复合物结合在MGMT、RAD51以及可能其他基因的启动子内。总体而言，RBBP4对包括肿瘤发生在内的关键细胞功能相关基因具有正向和负向调节作用。RBBP4/CBP/p300复合物可能为开发针对GBM和其他肿瘤的治疗增敏策略提供一个有趣的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/1b42ecee8a67/nihms761993f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/031074c42974/nihms761993f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/74adc5498ab0/nihms761993f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/9503c2dd8646/nihms761993f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/1b42ecee8a67/nihms761993f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/031074c42974/nihms761993f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/b5d351a90447/nihms761993f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/0fbd60c62599/nihms761993f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/23bf24441374/nihms761993f4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b36/4805508/1b42ecee8a67/nihms761993f7.jpg

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