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Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer

Resistance to targeted drugs is now a challenging clinical problem in the treatment of non-small cell lung cancer (NSCLC). So far, there are no approved targeted therapeutic drugs for patients with disease progression after the third-generation epidermal growth factor receptor-tyrosine kinase inhibi...

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Autores principales: Li, Hang, Muhetaer, Gulizeba, Xie, Yizi, Yao, Kainan, Ma, Qianqian, Guan, Huiting, Xing, Sizhong, Huang, Xiufang, Zhou, Jihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9719927/
https://www.ncbi.nlm.nih.gov/pubmed/36479196
http://dx.doi.org/10.3389/fphar.2022.1071365
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author Li, Hang
Muhetaer, Gulizeba
Xie, Yizi
Yao, Kainan
Ma, Qianqian
Guan, Huiting
Xing, Sizhong
Huang, Xiufang
Zhou, Jihong
author_facet Li, Hang
Muhetaer, Gulizeba
Xie, Yizi
Yao, Kainan
Ma, Qianqian
Guan, Huiting
Xing, Sizhong
Huang, Xiufang
Zhou, Jihong
author_sort Li, Hang
collection PubMed
description Resistance to targeted drugs is now a challenging clinical problem in the treatment of non-small cell lung cancer (NSCLC). So far, there are no approved targeted therapeutic drugs for patients with disease progression after the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib resistance (OR). Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive gene expression. In this study, we aimed to explore the potential pathogenic SEs and their driven genes in OR NSCLC. OR cell line was established by exposure of H1975 cells to incremental dosing of osimertinib. RNA-sequencing and H3K27ac ChIP-sequencing were used to identify the differential expressed genes (DEGs) and SEs in parental and resistant cells. Gene ontology analysis for the OR-specific SEs-associated genes showed that histone citrullination, protein citrullination, and peptidyl-arginine modification are the top three biological processes, and the DEGs involved in these biological processes, including peptidyl arginine deiminase 1 (PADI1), PADI2, and PADI3. Realtime-PCR and western blot detections confirmed these genes were highly expressed in OR cells. SE inhibitor decreases their expression, ensuring that SEs regulate their transcriptional expressions. The PADI inhibitor inhibited OR cells’ proliferation, invasion, and colony formation. This study demonstrates that SE-driven PADI family genes are potential biomarkers and targets for OR NSCLC.
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spelling pubmed-97199272022-12-06 Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer Li, Hang Muhetaer, Gulizeba Xie, Yizi Yao, Kainan Ma, Qianqian Guan, Huiting Xing, Sizhong Huang, Xiufang Zhou, Jihong Front Pharmacol Pharmacology Resistance to targeted drugs is now a challenging clinical problem in the treatment of non-small cell lung cancer (NSCLC). So far, there are no approved targeted therapeutic drugs for patients with disease progression after the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib resistance (OR). Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive gene expression. In this study, we aimed to explore the potential pathogenic SEs and their driven genes in OR NSCLC. OR cell line was established by exposure of H1975 cells to incremental dosing of osimertinib. RNA-sequencing and H3K27ac ChIP-sequencing were used to identify the differential expressed genes (DEGs) and SEs in parental and resistant cells. Gene ontology analysis for the OR-specific SEs-associated genes showed that histone citrullination, protein citrullination, and peptidyl-arginine modification are the top three biological processes, and the DEGs involved in these biological processes, including peptidyl arginine deiminase 1 (PADI1), PADI2, and PADI3. Realtime-PCR and western blot detections confirmed these genes were highly expressed in OR cells. SE inhibitor decreases their expression, ensuring that SEs regulate their transcriptional expressions. The PADI inhibitor inhibited OR cells’ proliferation, invasion, and colony formation. This study demonstrates that SE-driven PADI family genes are potential biomarkers and targets for OR NSCLC. Frontiers Media S.A. 2022-11-21 /pmc/articles/PMC9719927/ /pubmed/36479196 http://dx.doi.org/10.3389/fphar.2022.1071365 Text en Copyright © 2022 Li, Muhetaer, Xie, Yao, Ma, Guan, Xing, Huang and Zhou. 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 Pharmacology
Li, Hang
Muhetaer, Gulizeba
Xie, Yizi
Yao, Kainan
Ma, Qianqian
Guan, Huiting
Xing, Sizhong
Huang, Xiufang
Zhou, Jihong
Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title_full Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title_fullStr Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title_full_unstemmed Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title_short Identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
title_sort identification of super-enhancer-driven peptidyl arginine deiminases as potential biomarkers and therapeutic targets for osimertinib-resistant non-small cell lung cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9719927/
https://www.ncbi.nlm.nih.gov/pubmed/36479196
http://dx.doi.org/10.3389/fphar.2022.1071365
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