Abstract 7581: Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway

Abstract Objective: Lung cancer, particularly non-small cell lung cancer (NSCLC), continues to be a predominant contributor to global cancer-related mortality, with smoking emerging as a significant risk factor. Nicotine, which is one of the main chemicals from the tobacco smoke, is identified as carcinogen for lung cancer, especially for squamous carcinoma (LUSC). This study aims to investigates the intricate molecular mechanisms by which nicotine facilitates proliferation and migration in NSCLC through the c-Myc/EZH2 signaling pathway. Methods: Clinical tissue specimens were procured from surgical patients with lung cancer for immunohistochemical staining. Additionally, public databases were scrutinized to compare EZH2 expression between smokers and non-smokers. NSCLC cell lines underwent treatment with nicotine in a time- and concentration-dependent manner, and the impact on EZH2 was corroborated through Western Blot, Real-time PCR, and immunofluorescence staining. Proliferation and migration assays, encompassing CCK8 experiments, colony formation assays, EdU staining, and Transwell assays, were conducted to discern the effects of nicotine on NSCLC. Experimental techniques such as si-RNA and CHIP were deployed to investigate changes in c-Myc-mediated regulation of EZH2, elucidating the intricate role of the c-Myc/EZH2 pathway in nicotine-induced NSCLC proliferation and migration. Results: Smokers exhibited heightened EZH2 expression in tumor tissue compared to non-smokers. Nicotine treatment induced a concentration- and time-dependent upregulation of EZH2 in NSCLC cell lines. In 10 μM nicotine-treated NSCLC cells, concurrent treatment with 10 μM DZNep (EZH2 inhibitor) or si-EZH2 significantly augmented proliferation and migration. Moreover, the upregulation of EZH2 correlated with increased c-Myc expression, and siRNA-mediated c-Myc inhibition resulted in a corresponding reduction in EZH2 expression. Nicotine was identified as a promoter of NSCLC proliferation and migration through the c-Myc/EZH2 signaling pathway. This study establishes a robust association between nicotine and EZH2 in NSCLC cells, unveiling the novel regulatory axis of c-Myc/EZH2. Combined treatment with c-Myc and EZH2 inhibitors demonstrated efficacy in suppressing nicotine-induced promotion of NSCLC proliferation and migration. Conclusion: In summary, this study elucidates the mechanisms through which nicotine propels NSCLC development via the c-Myc/EZH2 pathway, providing a theoretical underpinning for future NSCLC treatment paradigms. The combined use of c-Myc and EZH2 inhibitors emerges as a promising therapeutic strategy, poised to inhibit nicotine-induced NSCLC proliferation and migration, offering enhanced treatment modalities for patients. Citation Format: Chen Ding, Hua Huang, Chen Chen, Yongwen Li, Hongyu Liu, Jun Chen. Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7581.