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HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second potential E3 ligase substrate, a critical cell cycle checkpoint...

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Autores principales: Moses, Niko, Zhang, Mu, Wu, Jheng-Yu, Hu, Chen, Xiang, Shengyan, Geng, Xinran, Chen, Yue, Bai, Wenlong, Zhang, You-Wei, Bepler, Gerold, Zhang, Xiaohong Mary
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600810/
https://www.ncbi.nlm.nih.gov/pubmed/33020410
http://dx.doi.org/10.3390/cells9102237
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author Moses, Niko
Zhang, Mu
Wu, Jheng-Yu
Hu, Chen
Xiang, Shengyan
Geng, Xinran
Chen, Yue
Bai, Wenlong
Zhang, You-Wei
Bepler, Gerold
Zhang, Xiaohong Mary
author_facet Moses, Niko
Zhang, Mu
Wu, Jheng-Yu
Hu, Chen
Xiang, Shengyan
Geng, Xinran
Chen, Yue
Bai, Wenlong
Zhang, You-Wei
Bepler, Gerold
Zhang, Xiaohong Mary
author_sort Moses, Niko
collection PubMed
description We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6’s E3 ligase activity.
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spelling pubmed-76008102020-11-01 HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1 Moses, Niko Zhang, Mu Wu, Jheng-Yu Hu, Chen Xiang, Shengyan Geng, Xinran Chen, Yue Bai, Wenlong Zhang, You-Wei Bepler, Gerold Zhang, Xiaohong Mary Cells Article We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6’s E3 ligase activity. MDPI 2020-10-04 /pmc/articles/PMC7600810/ /pubmed/33020410 http://dx.doi.org/10.3390/cells9102237 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Moses, Niko
Zhang, Mu
Wu, Jheng-Yu
Hu, Chen
Xiang, Shengyan
Geng, Xinran
Chen, Yue
Bai, Wenlong
Zhang, You-Wei
Bepler, Gerold
Zhang, Xiaohong Mary
HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title_full HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title_fullStr HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title_full_unstemmed HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title_short HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1
title_sort hdac6 regulates radiosensitivity of non-small cell lung cancer by promoting degradation of chk1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600810/
https://www.ncbi.nlm.nih.gov/pubmed/33020410
http://dx.doi.org/10.3390/cells9102237
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