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CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia

Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we explored the biological functions of cell cycle division-related gene 8 (CDCA8) in bladder cancer (BCa) cells in the hypoxic settings....

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Autores principales: Zhou, Qiang, Huang, Wei, Xiong, Jing, Guo, Biao, Wang, Xinghuan, Guo, Ju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562466/
https://www.ncbi.nlm.nih.gov/pubmed/37813876
http://dx.doi.org/10.1038/s41419-023-06189-x
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author Zhou, Qiang
Huang, Wei
Xiong, Jing
Guo, Biao
Wang, Xinghuan
Guo, Ju
author_facet Zhou, Qiang
Huang, Wei
Xiong, Jing
Guo, Biao
Wang, Xinghuan
Guo, Ju
author_sort Zhou, Qiang
collection PubMed
description Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we explored the biological functions of cell cycle division-related gene 8 (CDCA8) in bladder cancer (BCa) cells in the hypoxic settings. Specifically, we found that CDCA8 was significantly upregulated in BCa cell lines and clinical samples and its expression was positively correlated with advanced BCa stage, grade, and poor overall survival (OS). The expression of CDCA8 proteins was required for BCa cells to survive in the hypoxic condition. Mechanistically, CDCA8 stabilizes HIF1α by competing with PTEN for AKT binding, consequently leading to PTEN displacement and activation of the AKT/GSK3β signaling cascade that stimulates HIF1α protein stability. Significantly, HIF1α proteins bind to CDCA8 promoter for transcriptional activation, forming a positive-feedback loop to sustain BCa tumor cells under oxygen-deficient environment. Together, we defined CDCA8 as a key regulator for BCa cells to sense and prevail oxygen deprivation and as a novel BCa therapeutic target.
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spelling pubmed-105624662023-10-11 CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia Zhou, Qiang Huang, Wei Xiong, Jing Guo, Biao Wang, Xinghuan Guo, Ju Cell Death Dis Article Hypoxia is an essential hallmark of solid tumors and HIF1α is a central regulator of tumor cell adaptation and survival in the hypoxic environment. In this study, we explored the biological functions of cell cycle division-related gene 8 (CDCA8) in bladder cancer (BCa) cells in the hypoxic settings. Specifically, we found that CDCA8 was significantly upregulated in BCa cell lines and clinical samples and its expression was positively correlated with advanced BCa stage, grade, and poor overall survival (OS). The expression of CDCA8 proteins was required for BCa cells to survive in the hypoxic condition. Mechanistically, CDCA8 stabilizes HIF1α by competing with PTEN for AKT binding, consequently leading to PTEN displacement and activation of the AKT/GSK3β signaling cascade that stimulates HIF1α protein stability. Significantly, HIF1α proteins bind to CDCA8 promoter for transcriptional activation, forming a positive-feedback loop to sustain BCa tumor cells under oxygen-deficient environment. Together, we defined CDCA8 as a key regulator for BCa cells to sense and prevail oxygen deprivation and as a novel BCa therapeutic target. Nature Publishing Group UK 2023-10-09 /pmc/articles/PMC10562466/ /pubmed/37813876 http://dx.doi.org/10.1038/s41419-023-06189-x Text en © The Author(s) 2023 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, Qiang
Huang, Wei
Xiong, Jing
Guo, Biao
Wang, Xinghuan
Guo, Ju
CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title_full CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title_fullStr CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title_full_unstemmed CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title_short CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia
title_sort cdca8 promotes bladder cancer survival by stabilizing hif1α expression under hypoxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562466/
https://www.ncbi.nlm.nih.gov/pubmed/37813876
http://dx.doi.org/10.1038/s41419-023-06189-x
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