collected and organized the clinical data. restored gefitinib sensitivity both in vitro and in vivo, whereas CASC9 overexpression promoted gefitinib resistance. Mechanistically, CASC9 repressed the tumor suppressor DUSP1 by recruiting histone methyltransferase EZH2, thereby increasing the resistance to gefitinib. Furthermore, ectopic expression of DUSP1 increased gefitinib sensitivity by inactivating the ERK pathway. Our Rabbit Polyclonal to DOK4 results highlight the essential role of CASC9 in gefitinib resistance, suggesting that the CASC9/EZH2/DUSP1 axis might be a novel target for overcoming EGFR-TKI resistance in NSCLC. test. For the remaining assays, differences between groups were assessed by paired, two-tailed Students em t /em -test, Wilcoxons test, or em /em 2 test, as appropriate. em P /em ? ?0.05 was considered statistically significant. Supplementary information Supplementary Figure S1(3.3M, tif) Supplementary Figure S2(6.8M, tif) Supplementary Figure legends(13K, docx) Supplementary Table S1(49K, docx) Supplementary Table S2(12K, Ciprofloxacin hydrochloride hydrate xlsx) Supplementary Table S3(12M, xls) Acknowledgements This work was supported by grants from the National Natural Science Foundation of China (Nos. 81871871, 81802275 and 81902333), Key Research and Development plan (Social development) of science and technology department of Jiangsu Province (No. BE2019760); the Medical Innovation Team Foundation of Ciprofloxacin hydrochloride hydrate the Jiangsu Provincial Enhancement Health Project (No. CXTDA2017021); the Science and technology development fund of Nanjing Medical University (No. NMUB2018035); 123 advantageous disciplines, core technologies and 789 excellent Ciprofloxacin hydrochloride hydrate talent training plan of the Second Affiliated Hospital of Nanjing Medical University (No. 789ZYRC202090146); general topic of Nanjing medical science and technology development fund Ciprofloxacin hydrochloride hydrate (No.76). We thank Jane Charbonneau, DVM, from Liwen Bianji, Edanz Group China (http://www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript. Author contributions Z.X.W. and X.C. designed the study. Z.Y.C. and Q.N.C. designed the main experiments, detected the cells biological function, conducted the qRT-PCR assays, performed the statistical analysis, and wrote the manuscript. Z.X.C. and J.Y.G. participated in the design of the experiments and statistical analysis. J.L.H. established the animal model. T.Y.L. and J.Z.P. collected and organized the clinical data. J.Y.G. and W.Y.F. carried out the western blot assays. All authors read and approved the final version of the manuscript. Conflict of interest The authors declare that they have no conflict of interest. Footnotes Edited by I. Amelio Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. These authors jointly supervised this work and should be regarded as joint first authors: Zhenyao Chen, Qinnan Chen, Zhixiang Cheng, Jingyao Gu Contributor Information Xin Chen, Email: moc.361@5494nix_nehc. Zhaoxia Wang, Email: moc.621@66gnawaixoahz. Supplementary information Supplementary Information accompanies this paper at (10.1038/s41419-020-03047-y)..