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CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance...

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Autores principales: Ye, Xiang, Liu, Xiaochen, Gao, Min, Gong, Li, Tian, Fei, Shen, Yangli, Hu, Huili, Sun, Gongping, Zou, Yongxin, Gong, Yaoqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050354/
https://www.ncbi.nlm.nih.gov/pubmed/33869025
http://dx.doi.org/10.3389/fonc.2021.638802
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author Ye, Xiang
Liu, Xiaochen
Gao, Min
Gong, Li
Tian, Fei
Shen, Yangli
Hu, Huili
Sun, Gongping
Zou, Yongxin
Gong, Yaoqin
author_facet Ye, Xiang
Liu, Xiaochen
Gao, Min
Gong, Li
Tian, Fei
Shen, Yangli
Hu, Huili
Sun, Gongping
Zou, Yongxin
Gong, Yaoqin
author_sort Ye, Xiang
collection PubMed
description Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance.
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spelling pubmed-80503542021-04-17 CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription Ye, Xiang Liu, Xiaochen Gao, Min Gong, Li Tian, Fei Shen, Yangli Hu, Huili Sun, Gongping Zou, Yongxin Gong, Yaoqin Front Oncol Oncology Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance. Frontiers Media S.A. 2021-04-02 /pmc/articles/PMC8050354/ /pubmed/33869025 http://dx.doi.org/10.3389/fonc.2021.638802 Text en Copyright © 2021 Ye, Liu, Gao, Gong, Tian, Shen, Hu, Sun, Zou and Gong https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Ye, Xiang
Liu, Xiaochen
Gao, Min
Gong, Li
Tian, Fei
Shen, Yangli
Hu, Huili
Sun, Gongping
Zou, Yongxin
Gong, Yaoqin
CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title_full CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title_fullStr CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title_full_unstemmed CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title_short CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription
title_sort cul4b promotes temozolomide resistance in gliomas by epigenetically repressing cdnk1a transcription
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050354/
https://www.ncbi.nlm.nih.gov/pubmed/33869025
http://dx.doi.org/10.3389/fonc.2021.638802
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