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Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditio...

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Autores principales: Zhou, Bingluo, Zhu, Yiran, Xu, Wenxia, Zhou, Qiyin, Tan, Linghui, Zhu, Liyuan, Chen, Hui, Feng, Lifeng, Hou, Tianlun, Wang, Xian, Chen, Dingwei, Jin, Hongchuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719622/
https://www.ncbi.nlm.nih.gov/pubmed/34977006
http://dx.doi.org/10.3389/fcell.2021.741736
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author Zhou, Bingluo
Zhu, Yiran
Xu, Wenxia
Zhou, Qiyin
Tan, Linghui
Zhu, Liyuan
Chen, Hui
Feng, Lifeng
Hou, Tianlun
Wang, Xian
Chen, Dingwei
Jin, Hongchuan
author_facet Zhou, Bingluo
Zhu, Yiran
Xu, Wenxia
Zhou, Qiyin
Tan, Linghui
Zhu, Liyuan
Chen, Hui
Feng, Lifeng
Hou, Tianlun
Wang, Xian
Chen, Dingwei
Jin, Hongchuan
author_sort Zhou, Bingluo
collection PubMed
description Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.
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spelling pubmed-87196222022-01-01 Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B Zhou, Bingluo Zhu, Yiran Xu, Wenxia Zhou, Qiyin Tan, Linghui Zhu, Liyuan Chen, Hui Feng, Lifeng Hou, Tianlun Wang, Xian Chen, Dingwei Jin, Hongchuan Front Cell Dev Biol Cell and Developmental Biology Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment. Frontiers Media S.A. 2021-12-17 /pmc/articles/PMC8719622/ /pubmed/34977006 http://dx.doi.org/10.3389/fcell.2021.741736 Text en Copyright © 2021 Zhou, Zhu, Xu, Zhou, Tan, Zhu, Chen, Feng, Hou, Wang, Chen and Jin. 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 Cell and Developmental Biology
Zhou, Bingluo
Zhu, Yiran
Xu, Wenxia
Zhou, Qiyin
Tan, Linghui
Zhu, Liyuan
Chen, Hui
Feng, Lifeng
Hou, Tianlun
Wang, Xian
Chen, Dingwei
Jin, Hongchuan
Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title_full Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title_fullStr Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title_full_unstemmed Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title_short Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B
title_sort hypoxia stimulates sumoylation-dependent stabilization of kdm5b
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719622/
https://www.ncbi.nlm.nih.gov/pubmed/34977006
http://dx.doi.org/10.3389/fcell.2021.741736
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