Liang Hengxing, Zhang Chunmin, Hu Minxin, Hu Fang, Wang Saihui, Wei Wei, Hu Wen
Department of Thoracic Surgery, Guilin Hospital of the Second Xiangya Hospital CSU, Guilin, China.
Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
Mol Carcinog. 2025 Jan;64(1):57-71. doi: 10.1002/mc.23826. Epub 2024 Oct 10.
The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (mA) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the mA modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated mA modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the mA modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 mA methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated mA modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway.
X盒结合蛋白1（XBP1）是内质网应激反应过程中的一种重要转录因子，据报道其在非小细胞肺癌（NSCLC）的肿瘤发生和发展中作为癌基因发挥作用。然而，XBP1表达在NSCLC进展中的调控机制报道较少。N6-甲基腺苷（m⁶A）RNA修饰是一种新兴的基因表达表观遗传调控机制。本研究旨在探讨m⁶A修饰在NSCLC中对XBP1表达的调控作用。我们确定XBP1是A549和PC9细胞中ALKBH5介导的m⁶A修饰的下游靶点。敲低ALKBH5会增加XBP1 mRNA的m⁶A修饰和稳定性，而过表达ALKBH5则产生相反的效果。此外，IGF2BP3被证实是XBP1 m⁶A甲基化的读取蛋白，并能增强XBP1 mRNA的稳定性。另外，敲低IGF2BP3可显著逆转由ALKBH5缺失介导的XBP1稳定性增加。体内和体外实验表明，ALKBH5/IGF2BP3通过上调XBP1表达促进NSCLC细胞的增殖、迁移和侵袭。此外，我们还表明XBP1通过激活IL-6-JAK-STAT3信号通路促进NSCLC细胞的增殖、迁移和侵袭。我们的研究表明，ALKBH5介导的XBP1的m⁶A修饰通过IL-6-JAK-STAT3途径促进NSCLC进展。
