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ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma

Bortezomib, a proteasome inhibitor, proved potent in the treatment of recurrent multiple myeloma or mantle cell lymphoma. However, slow progress was made when it was applied to treat solid tumors. We discovered that different head and neck squamous cell carcinoma (HNSCC) cell lines had significantly...

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Autores principales: Zhou, Peng, Zhang, Caiyun, Song, Xianmin, Zhang, Dadong, Zhu, Minhui, Zheng, Hongliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994767/
https://www.ncbi.nlm.nih.gov/pubmed/35397613
http://dx.doi.org/10.1038/s41419-022-04790-0
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author Zhou, Peng
Zhang, Caiyun
Song, Xianmin
Zhang, Dadong
Zhu, Minhui
Zheng, Hongliang
author_facet Zhou, Peng
Zhang, Caiyun
Song, Xianmin
Zhang, Dadong
Zhu, Minhui
Zheng, Hongliang
author_sort Zhou, Peng
collection PubMed
description Bortezomib, a proteasome inhibitor, proved potent in the treatment of recurrent multiple myeloma or mantle cell lymphoma. However, slow progress was made when it was applied to treat solid tumors. We discovered that different head and neck squamous cell carcinoma (HNSCC) cell lines had significantly different sensitivities to bortezomib, and also demonstrated that individual relatively sensitive HNSCC cell lines had fewer ΔNp63α expressions. Based on these findings, we speculated that ΔNp63α may be a key factor in the resistance of HNSCC cells to bortezomib. ΔNp63α knockdown made HNSCC more sensitive to bortezomib, while ΔNp63α overexpression made it more resistant. RNA sequencing (RNA-seq) analysis of ΔNp63α-knockdown cells revealed clear alterations in the subset of genes that were associated with oxidative stress and antioxidant defense. The gene CYGB was downregulated significantly. CHIP-seq detection showed that CYGB was the transcriptional regulatory site of ΔNp63α. CHIP-PCR showed evidence of ΔNp63α binding. The detection of the dual-luciferase reporter gene demonstrated that ΔNp63α significantly enhanced the CYGB promoter activity. Furthermore, we confirmed that CYGB plays a role in clearing excess ROS induced by bortezomib to inhibit HNSCC apoptosis. Consequently, ΔNp63α regulated the expression of CYGB in HNSCC. CYGB was the target of transcription regulation of ΔNp63α. It reduced apoptosis by clearing excess ROS produced by bortezomib, and thus exerted drug resistance.
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spelling pubmed-89947672022-04-27 ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma Zhou, Peng Zhang, Caiyun Song, Xianmin Zhang, Dadong Zhu, Minhui Zheng, Hongliang Cell Death Dis Article Bortezomib, a proteasome inhibitor, proved potent in the treatment of recurrent multiple myeloma or mantle cell lymphoma. However, slow progress was made when it was applied to treat solid tumors. We discovered that different head and neck squamous cell carcinoma (HNSCC) cell lines had significantly different sensitivities to bortezomib, and also demonstrated that individual relatively sensitive HNSCC cell lines had fewer ΔNp63α expressions. Based on these findings, we speculated that ΔNp63α may be a key factor in the resistance of HNSCC cells to bortezomib. ΔNp63α knockdown made HNSCC more sensitive to bortezomib, while ΔNp63α overexpression made it more resistant. RNA sequencing (RNA-seq) analysis of ΔNp63α-knockdown cells revealed clear alterations in the subset of genes that were associated with oxidative stress and antioxidant defense. The gene CYGB was downregulated significantly. CHIP-seq detection showed that CYGB was the transcriptional regulatory site of ΔNp63α. CHIP-PCR showed evidence of ΔNp63α binding. The detection of the dual-luciferase reporter gene demonstrated that ΔNp63α significantly enhanced the CYGB promoter activity. Furthermore, we confirmed that CYGB plays a role in clearing excess ROS induced by bortezomib to inhibit HNSCC apoptosis. Consequently, ΔNp63α regulated the expression of CYGB in HNSCC. CYGB was the target of transcription regulation of ΔNp63α. It reduced apoptosis by clearing excess ROS produced by bortezomib, and thus exerted drug resistance. Nature Publishing Group UK 2022-04-09 /pmc/articles/PMC8994767/ /pubmed/35397613 http://dx.doi.org/10.1038/s41419-022-04790-0 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhou, Peng
Zhang, Caiyun
Song, Xianmin
Zhang, Dadong
Zhu, Minhui
Zheng, Hongliang
ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title_full ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title_fullStr ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title_full_unstemmed ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title_short ΔNp63α promotes Bortezomib resistance via the CYGB–ROS axis in head and neck squamous cell carcinoma
title_sort δnp63α promotes bortezomib resistance via the cygb–ros axis in head and neck squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994767/
https://www.ncbi.nlm.nih.gov/pubmed/35397613
http://dx.doi.org/10.1038/s41419-022-04790-0
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