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FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway

Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific...

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Autores principales: Zhang, Yaqi, Wang, Yinu, Zhao, Guangyuan, Tanner, Edward J., Adli, Mazhar, Matei, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106354/
https://www.ncbi.nlm.nih.gov/pubmed/35349489
http://dx.doi.org/10.1172/JCI151591
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author Zhang, Yaqi
Wang, Yinu
Zhao, Guangyuan
Tanner, Edward J.
Adli, Mazhar
Matei, Daniela
author_facet Zhang, Yaqi
Wang, Yinu
Zhao, Guangyuan
Tanner, Edward J.
Adli, Mazhar
Matei, Daniela
author_sort Zhang, Yaqi
collection PubMed
description Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1α (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs.
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spelling pubmed-91063542022-05-18 FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway Zhang, Yaqi Wang, Yinu Zhao, Guangyuan Tanner, Edward J. Adli, Mazhar Matei, Daniela J Clin Invest Research Article Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1α (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs. American Society for Clinical Investigation 2022-05-16 2022-05-16 /pmc/articles/PMC9106354/ /pubmed/35349489 http://dx.doi.org/10.1172/JCI151591 Text en © 2022 Zhang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhang, Yaqi
Wang, Yinu
Zhao, Guangyuan
Tanner, Edward J.
Adli, Mazhar
Matei, Daniela
FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title_full FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title_fullStr FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title_full_unstemmed FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title_short FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
title_sort foxk2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106354/
https://www.ncbi.nlm.nih.gov/pubmed/35349489
http://dx.doi.org/10.1172/JCI151591
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