近日，天津医科大学教授陈军及其团队的论文发现了尼古丁通过调节OTUB1-c-Myc-EZH2轴促进非小细胞肺癌的进展和转移。相关论文于2025年4月1日发表于国际顶尖学术期刊《中国药理学报》杂志上。

吸烟已被确定为非小细胞肺癌（NSCLC）发生和发展的主要危险因素。尼古丁作为烟草烟雾的关键成分，被认为在促进非小细胞肺癌的生长和进展中起着重要作用。EZH2是吸烟者肿瘤组织中高度表达的表观遗传调控因子。

然而，尼古丁是否以及如何调节EZH2的表达及其机制尚不清楚。以生物信息学分析和免疫组织化学为主题，比较吸烟者和非吸烟者NSCLC样本中EZH2的表达。采用蛋白质印迹、实时定量PCR和免疫荧光法证实尼古丁对EZH2表达的影响。采用细胞计数试剂盒-8法、集落形成法、5-乙基-2-脱氧尿苷染色法和Transwell法分析siRNA或EZH2抑制剂处理A549和H1650细胞的增殖和转移情况。采用实时定量PCR和染色质免疫沉淀法，通过c-Myc评估尼古丁对EZH2转录物水平的调节作用。通过共免疫沉淀和泛素化实验来评估OTUB1对c-Myc的去泛素化作用。最后，以裸鼠模型为主题，评估c-Myc和EZH2抑制剂联合使用对体内肿瘤增殖和转移的影响。生物信息学和免疫组化分析表明，EZH2在NSCLC患者中表达水平相对较高。尼古丁上调EZH2的表达，促进肺癌细胞的增殖和转移能力。DZNep或EPZ6438、EZH2抑制剂或siRNA抑制EZH2可显著降低尼古丁治疗诱导的NSCLC细胞的增殖和转移能力。

此外，研究发现尼古丁诱导OTUB1表达，通过去泛素化作用稳定c-Myc蛋白，并使c-Myc介导的EZH2转录激活。

此外，c-Myc抑制剂10058-F4在体外和体内均与EZH2抑制剂DZNep具有协同抑制NSCLC细胞增殖和转移的作用。尼古丁通过OTUB1介导的去泛素化调控c-Myc/EZH2信号通路，从而促进NSCLC细胞的增殖和转移。本研究揭示了尼古丁在非小细胞肺癌发生发展中的新的分子机制，为今后的治疗策略提供理论基础。

附：英文原文

Title: Nicotine promotes the progression and metastasis of non-small cell lung cancer by modulating the OTUB1-c-Myc-EZH2 axis

Author: Huang, Hua, Ding, Chen, Zhao, Wen-hao, Zhang, Hong-bing, Zhao, Ze-xia, Li, Xuan-guang, Wang, Ying-jie, Chen, Pei-jie, Li, Bo-shi, Li, Xue-bing, Li, Yong-wen, Liu, Hong-yu, Chen, Jun

Issue&Volume: 2025-04-01

Abstract: Smoking has been identified as a major risk factor for the development and progression of non-small cell lung cancer (NSCLC). As a key component of tobacco smoke, nicotine is believed to play a significant role in promoting NSCLC growth and progression. EZH2 is an epigenetic regulator highly expressed in the tumor tissues of smokers. However, whether and how nicotine regulates the expression of EZH2 and the underlying mechanisms remain unclear. Bioinformatics analysis and immunohistochemistry were used to compare the expression of EZH2 in NSCLC samples between smokers and nonsmokers. Western blotting, real-time quantitative PCR, and immunofluorescence were employed to confirm the effects of nicotine on EZH2 expression. Cell Counting Kit-8 assays, colony formation assays, 5-ethynyl-2-deoxyuridine staining, and Transwell assays were conducted to analyze the proliferation and metastasis of A549 and H1650 cells treated with siRNA or EZH2 inhibitors. Real-time quantitative PCR and chromatin immunoprecipitation assays were performed to assess the regulatory effect of nicotine on EZH2 transcript levels via c-Myc. Coimmunoprecipitation and ubiquitination assays were used to assess the deubiquitination of c-Myc by OTUB1. Finally, a nude mouse model was used to evaluate the impact of combined c-Myc and EZH2 inhibitors on tumor proliferation and metastasis in vivo. EZH2 is expressed at relatively high levels in NSCLC patients, as determined by both bioinformatic and IHC analyses. Nicotine upregulates EZH2 expression and promotes the proliferation and metastatic ability of lung cancer cells. Inhibition of EZH2 with either DZNep or EPZ6438, EZH2 inhibitors, or siRNA significantly decreased the proliferative and metastatic capacity of NSCLC cells induced by nicotine treatment. Moreover, the study revealed that nicotine induces OTUB1 expression, stabilizes the c-Myc protein via deubiquitination, and enables c-Myc-mediated transcriptional activation of EZH2. Furthermore, the c-Myc inhibitor 10058-F4 exhibited synergistic effects with the EZH2 inhibitor DZNep in suppressing NSCLC cell proliferation and metastasis both in vitro and in vivo.Nicotine regulates the c-Myc/EZH2 signaling pathway via OTUB1-mediated deubiquitination, thereby promoting the proliferation and metastasis of NSCLC cells. This research reveals novel molecular mechanisms of nicotine in the development of NSCLC, providing a theoretical foundation for future therapeutic strategies.

DOI: 10.1038/s41401-025-01527-5

Source: https://www.nature.com/articles/s41401-025-01527-5