Chen Huanxiang, Xiao Nan, Zhang Chenxing, Li Yang, Zhao Xiangzhuan, Zhang Ruike, Bai Lu, Kang Qiaozhen, Wan Junhu, Liu Hongyang
Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of General Surgery, Zhecheng People's Hospital, Shangqiu, Henan, China.
J Transl Med. 2025 Feb 26;23(1):233. doi: 10.1186/s12967-025-06241-8.
The Jumonji domain-containing protein 6 (JMJD6), a histone arginine demethylase, is known to have a multifaceted and significant role on cancer progression. However, the specific function and mechanism of JMJD6 in non-small cell lung cancer (NSCLC) have yet to be fully elucidated.
The elevated expression of JMJD6 in lung cancer tissues was confirmed through a combination of bioinformatics and immunohistochemical analysis. Utilizing lung cancer cell lines H460, H157, A549, and H1299, we further investigated the impact of JMJD6 on various cellular processes such as ferroptosis, proliferation, migration, and invasion both in vivo and in vitro. The acetylation of JMJD6 was characterized using immunoprecipitation, co-immunoprecipitation, GST pull down, and immunofluorescence techniques. The regulatory role of JMJD6 acetylation in ferroptosis was assessed by measuring levels of ROS, MDA, and JC-1. WB, qRT-PCR, ChIP and MeRIP techniques were employed to investigate the relationship between the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis.
This study revealed elevated levels of JMJD6 in tumor tissue, with high expression correlating strongly with advanced clinical stage in lung cancer patients, and identified JMJD6 as a significantly poor prognostic factor for lung cancer. Functional experiments verified that ectopic overexpression of JMJD6 enhanced the proliferation and migratory capacities of lung cancer cells, while JMJD6 knockdown showed opposite effects. We further find that JMJD6 functions as a negative modulator in regulating ferroptosis process. Mechanistically, JMJD6 affects METTL14 expression in an arginine demethylase dependent manner, and mediates m6A modification of SLC3A2 to regulate its expression level, thereby affecting the sensitivity of lung cancer cells to ferroptosis. Besides, our findings indicate that acetyltransferase p300/CBP associated factor (PCAF) interacts with and acetylates JMJD6 at lysine 375. Acetylation weakens the activity of JMJD6 demethylase, thereby enhancing METTL14 expression and affecting its mediated m6A modification to regulate SLC3A2. Acetylation at lysine 375 also augment the modulation of ferroptosis in lung cancer cells by JMJD6, consequently impeding the lung cancer progression.
Taken together, we elucidated the JMJD6 acetylation/METTL14/m6A/SLC3A2 axis as a key mediator of lung cancer progression, indicating that JMJD6 may serve as a potentially prognostic biomarker and therapeutic target for NSCLC.
含Jumonji结构域蛋白6（JMJD6）是一种组蛋白精氨酸去甲基化酶，已知在癌症进展中具有多方面的重要作用。然而，JMJD6在非小细胞肺癌（NSCLC）中的具体功能和机制尚未完全阐明。
通过生物信息学和免疫组织化学分析相结合，证实肺癌组织中JMJD6表达升高。利用肺癌细胞系H460、H157、A549和H1299，我们进一步研究了JMJD6在体内外对铁死亡、增殖、迁移和侵袭等各种细胞过程的影响。使用免疫沉淀、免疫共沉淀、GST下拉和免疫荧光技术对JMJD6的乙酰化进行了表征。通过测量ROS、MDA和JC-1水平评估JMJD6乙酰化在铁死亡中的调节作用。采用WB、qRT-PCR、ChIP和MeRIP技术研究JMJD6乙酰化/METTL14/m6A/SLC3A2轴之间的关系。
本研究揭示肿瘤组织中JMJD6水平升高，其高表达与肺癌患者的晚期临床分期密切相关，并确定JMJD6是肺癌的一个显著不良预后因素。功能实验证实，JMJD6的异位过表达增强了肺癌细胞的增殖和迁移能力，而JMJD6敲低则显示出相反的效果。我们进一步发现JMJD6在调节铁死亡过程中起负调节作用。机制上，JMJD6以精氨酸去甲基化酶依赖的方式影响METTL14表达，并介导SLC3A2的m6A修饰以调节其表达水平，从而影响肺癌细胞对铁死亡的敏感性。此外，我们的研究结果表明，乙酰转移酶p300/CBP相关因子（PCAF）与JMJD6相互作用并在赖氨酸375处使其乙酰化。乙酰化减弱了JMJD6去甲基化酶的活性，从而增强METTL14表达并影响其介导的m6A修饰以调节SLC3A2。赖氨酸375处的乙酰化还增强了JMJD6对肺癌细胞铁死亡的调节作用，从而阻碍肺癌进展。
综上所述，我们阐明了JMJD6乙酰化/METTL14/m6A/SLC3A2轴是肺癌进展的关键介质，表明JMJD6可能作为NSCLC潜在的预后生物标志物和治疗靶点。
