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The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes

Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis’s specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone...

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Autores principales: Shait Mohammed, Mohammed Razeeth, Zamzami, Mazin, Choudhry, Hani, Ahmed, Firoz, Ateeq, Bushra, Khan, Mohammad Imran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847600/
https://www.ncbi.nlm.nih.gov/pubmed/35186918
http://dx.doi.org/10.3389/fcell.2022.780176
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author Shait Mohammed, Mohammed Razeeth
Zamzami, Mazin
Choudhry, Hani
Ahmed, Firoz
Ateeq, Bushra
Khan, Mohammad Imran
author_facet Shait Mohammed, Mohammed Razeeth
Zamzami, Mazin
Choudhry, Hani
Ahmed, Firoz
Ateeq, Bushra
Khan, Mohammad Imran
author_sort Shait Mohammed, Mohammed Razeeth
collection PubMed
description Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis’s specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone demethylases are involved in promoting or resisting anoikis remains elusive. We screened the major histone demethylases and found that both H3K27 histone demethylases, namely, KDM6A/B were highly expressed during ECM detachment. Inhibition of the KDM6A/B activity by using a specific inhibitor results in reduced sphere formation capacity and increased apoptosis. Knockout of KDM6B leads to the loss of stem cell properties in solitary cells. Furthermore, we found that KDM6B maintains stemness by transcriptionally regulating the expression of stemness genes SOX2, SOX9, and CD44 in detached cells. KDM6B occupies the promoter region of both SOX2 and CD44 to regulate their expression epigenetically. We also noticed an increased occupancy of the HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in detached cancer cells. This observation was further strengthened as we found a significant positive association in the expression of both KDM6B and HIF1α in various cancer types. Overall, our results reveal a novel transcriptional program that regulates resistance against anoikis and maintains stemness-like properties.
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spelling pubmed-88476002022-02-17 The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes Shait Mohammed, Mohammed Razeeth Zamzami, Mazin Choudhry, Hani Ahmed, Firoz Ateeq, Bushra Khan, Mohammad Imran Front Cell Dev Biol Cell and Developmental Biology Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis’s specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone demethylases are involved in promoting or resisting anoikis remains elusive. We screened the major histone demethylases and found that both H3K27 histone demethylases, namely, KDM6A/B were highly expressed during ECM detachment. Inhibition of the KDM6A/B activity by using a specific inhibitor results in reduced sphere formation capacity and increased apoptosis. Knockout of KDM6B leads to the loss of stem cell properties in solitary cells. Furthermore, we found that KDM6B maintains stemness by transcriptionally regulating the expression of stemness genes SOX2, SOX9, and CD44 in detached cells. KDM6B occupies the promoter region of both SOX2 and CD44 to regulate their expression epigenetically. We also noticed an increased occupancy of the HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in detached cancer cells. This observation was further strengthened as we found a significant positive association in the expression of both KDM6B and HIF1α in various cancer types. Overall, our results reveal a novel transcriptional program that regulates resistance against anoikis and maintains stemness-like properties. Frontiers Media S.A. 2022-02-02 /pmc/articles/PMC8847600/ /pubmed/35186918 http://dx.doi.org/10.3389/fcell.2022.780176 Text en Copyright © 2022 Shait Mohammed, Zamzami, Choudhry, Ahmed, Ateeq and Khan. 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
Shait Mohammed, Mohammed Razeeth
Zamzami, Mazin
Choudhry, Hani
Ahmed, Firoz
Ateeq, Bushra
Khan, Mohammad Imran
The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title_full The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title_fullStr The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title_full_unstemmed The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title_short The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
title_sort histone h3k27me3 demethylases kdm6a/b resist anoikis and transcriptionally regulate stemness-related genes
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847600/
https://www.ncbi.nlm.nih.gov/pubmed/35186918
http://dx.doi.org/10.3389/fcell.2022.780176
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