Cargando…
Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15
The Jumonji C domain-containing family of histone lysine demethylases (Jumonji KDMs) have emerged as promising cancer therapy targets. These enzymes remove methyl groups from various histone lysines and, in turn, regulate processes including chromatin compaction, gene transcription, and DNA repair....
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812751/ https://www.ncbi.nlm.nih.gov/pubmed/35100078 http://dx.doi.org/10.1080/15384047.2021.2020060 |
_version_ | 1784644722009047040 |
---|---|
author | Duan, Lei Perez, Ricardo E. Calhoun, Sarah Maki, Carl G. |
author_facet | Duan, Lei Perez, Ricardo E. Calhoun, Sarah Maki, Carl G. |
author_sort | Duan, Lei |
collection | PubMed |
description | The Jumonji C domain-containing family of histone lysine demethylases (Jumonji KDMs) have emerged as promising cancer therapy targets. These enzymes remove methyl groups from various histone lysines and, in turn, regulate processes including chromatin compaction, gene transcription, and DNA repair. Small molecule inhibitors of Jumonji KDMs have shown promise in preclinical studies against non-small cell lung cancer (NSCLC) and other cancers. However, how these inhibitors influence cancer therapy responses and/or DNA repair is incompletely understood. In this study, we established cell line and PDX tumor model systems of cisplatin and paclitaxel-resistant NSCLC. We showed that resistant cells and tumors express high levels of Jumonji-KDMs. Knockdown of individual KDMs or treatment with a pan-Jumonji KDM inhibitor sensitized the cells and tumors to cisplatin and paclitaxel and blocked NSCLC in vivo tumor growth. Mechanistically, we found inhibition of Jumonji-KDMs triggers APC/Cdh1-dependent degradation of CtIP and PAF15, two DNA repair proteins that promote repair of cisplatin and paclitaxel-induced DNA lesions. Knockdown of CtIP and PAF15 sensitized resistant cells to cisplatin, indicating their degradation when Jumonji KDMs are inhibited contributes to cisplatin sensitivity. Our results support the idea that Jumonji-KDMs are a targetable barrier to effective therapy responses in NSCLC. Inhibition of Jumonji KDMs increases therapy (cisplatin/paclitaxel) sensitivity in NSCLC cells, at least in part, by promoting APC/Cdh1-dependent degradation of CtIP and PAF15. |
format | Online Article Text |
id | pubmed-8812751 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-88127512022-02-04 Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 Duan, Lei Perez, Ricardo E. Calhoun, Sarah Maki, Carl G. Cancer Biol Ther Research Paper The Jumonji C domain-containing family of histone lysine demethylases (Jumonji KDMs) have emerged as promising cancer therapy targets. These enzymes remove methyl groups from various histone lysines and, in turn, regulate processes including chromatin compaction, gene transcription, and DNA repair. Small molecule inhibitors of Jumonji KDMs have shown promise in preclinical studies against non-small cell lung cancer (NSCLC) and other cancers. However, how these inhibitors influence cancer therapy responses and/or DNA repair is incompletely understood. In this study, we established cell line and PDX tumor model systems of cisplatin and paclitaxel-resistant NSCLC. We showed that resistant cells and tumors express high levels of Jumonji-KDMs. Knockdown of individual KDMs or treatment with a pan-Jumonji KDM inhibitor sensitized the cells and tumors to cisplatin and paclitaxel and blocked NSCLC in vivo tumor growth. Mechanistically, we found inhibition of Jumonji-KDMs triggers APC/Cdh1-dependent degradation of CtIP and PAF15, two DNA repair proteins that promote repair of cisplatin and paclitaxel-induced DNA lesions. Knockdown of CtIP and PAF15 sensitized resistant cells to cisplatin, indicating their degradation when Jumonji KDMs are inhibited contributes to cisplatin sensitivity. Our results support the idea that Jumonji-KDMs are a targetable barrier to effective therapy responses in NSCLC. Inhibition of Jumonji KDMs increases therapy (cisplatin/paclitaxel) sensitivity in NSCLC cells, at least in part, by promoting APC/Cdh1-dependent degradation of CtIP and PAF15. Taylor & Francis 2022-01-31 /pmc/articles/PMC8812751/ /pubmed/35100078 http://dx.doi.org/10.1080/15384047.2021.2020060 Text en © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Duan, Lei Perez, Ricardo E. Calhoun, Sarah Maki, Carl G. Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title | Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title_full | Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title_fullStr | Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title_full_unstemmed | Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title_short | Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15 |
title_sort | inhibitors of jumonji c domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through apc/cdh1-dependent degradation of ctip and paf15 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812751/ https://www.ncbi.nlm.nih.gov/pubmed/35100078 http://dx.doi.org/10.1080/15384047.2021.2020060 |
work_keys_str_mv | AT duanlei inhibitorsofjumonjicdomaincontaininghistonelysinedemethylasesovercomecisplatinandpaclitaxelresistanceinnonsmallcelllungcancerthroughapccdh1dependentdegradationofctipandpaf15 AT perezricardoe inhibitorsofjumonjicdomaincontaininghistonelysinedemethylasesovercomecisplatinandpaclitaxelresistanceinnonsmallcelllungcancerthroughapccdh1dependentdegradationofctipandpaf15 AT calhounsarah inhibitorsofjumonjicdomaincontaininghistonelysinedemethylasesovercomecisplatinandpaclitaxelresistanceinnonsmallcelllungcancerthroughapccdh1dependentdegradationofctipandpaf15 AT makicarlg inhibitorsofjumonjicdomaincontaininghistonelysinedemethylasesovercomecisplatinandpaclitaxelresistanceinnonsmallcelllungcancerthroughapccdh1dependentdegradationofctipandpaf15 |