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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

Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Li, Hang;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Muhetaer, Gulizeba;
Affiliation
The First Affiliated Hospital of Guangzhou University of Chinese Medicine ,Guangzhou ,China
Xie, Yizi;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Yao, Kainan;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Ma, Qianqian;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Guan, Huiting;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Xing, Sizhong;
Affiliation
The First Affiliated Hospital of Guangzhou University of Chinese Medicine ,Guangzhou ,China
Huang, Xiufang;
Affiliation
Shenzhen Bao’an Traditional Chinese Medicine Hospital ,Guangzhou University of Chinese Medicine ,Shenzhen ,China
Zhou, Jihong

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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License Holder: Copyright © 2022 Li, Muhetaer, Xie, Yao, Ma, Guan, Xing, Huang and Zhou.

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