Yao Xufeng, Chai Qian, Ma Yuhao, Li Guomeng, Jia Tiantian, Zhang Xiaohang, Xia Tao, Wei Xiaozheng, Feng Xueyi, Zhang Yanke, Zhang Yaqiang, Wang Xueqin, Han Danye, Li Zongwei, Zhao Lei, Dai Qian
School of Life Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China.
Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230012, Anhui Province, China.
Cell Biosci. 2025 Aug 11;15(1):116. doi: 10.1186/s13578-025-01455-1.
Although aerobic glycolysis contributes to malignancy and drug resistance in human cancers, the vital regulators of glycolysis in lung adenocarcinoma (LUAD) remain largely unknown. Transcription factor AF4/FMR2 family member 4 (AFF4) is the scaffolding protein of the super elongation complex (SEC) and regulates the transcription of cancer-related genes. However, the role of AFF4 in glycolysis and LUAD development remains unidentified.
AFF4 expression was assessed in LUAD cells and tissues using bioinformatics analysis, western blotting, and immunohistochemical staining. Changes in cell proliferation, migration, and invasion were determined using in vitro and in vivo loss- and gain-of-function assays. Additionally, glycolysis levels were assessed using metabolite determination assays of glucose and lactate. The underlying mechanisms were elucidated via transcriptome sequencing, cleavage under targets (CUT) &Tag, dual-luciferase reporting assay, and a series of rescue experiments.
AFF4 was overexpressed in wild-type and cisplatin-resistant LUAD cells and acted as a prognostic indicator in patients with LUAD. AFF4 enhanced the tumorigenic characteristics and cisplatin resistance of LUAD cells by accelerating glycolysis. Meanwhile, glycolysis inhibition restored the AFF4 overexpression-induced increase in cell proliferation and migration and rendered AFF4-overexpressing LUAD cells sensitive to cisplatin. Mechanistically, AFF4 promoted glycolysis by modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ signaling pathway. AFF4 downregulated phosphatase and tensin homolog (PTEN) expression by directly targeting its promoter, activating the PI3K/AKT/mTOR pathway. Additionally, transcription factor Yin Yang 1 (YY1) upregulated AFF4 by binding to its promoter, further influencing glycolysis and oncogenesis.
AFF4 drives metabolic reprogramming, tumor progression, and cisplatin resistance through PTEN-mediated activation of the PI3K/AKT/mTOR signaling pathway, highlighting AFF4 inhibition as a potential therapeutic strategy in LUAD.
尽管有氧糖酵解在人类癌症的发生及耐药性中起作用，但肺腺癌（LUAD）中糖酵解的关键调节因子仍 largely 未知。转录因子 AF4/FMR2 家族成员 4（AFF4）是超级延伸复合物（SEC）的支架蛋白，调节癌症相关基因的转录。然而，AFF4 在糖酵解及 LUAD 发展中的作用仍未明确。
使用生物信息学分析、蛋白质免疫印迹和免疫组织化学染色评估 LUAD 细胞和组织中 AFF4 的表达。使用体外和体内功能丧失和功能获得实验确定细胞增殖、迁移和侵袭的变化。此外，使用葡萄糖和乳酸的代谢物测定实验评估糖酵解水平。通过转录组测序、靶点切割（CUT）&Tag、双荧光素酶报告实验和一系列挽救实验阐明潜在机制。
AFF4 在野生型和顺铂耐药的 LUAD 细胞中过表达，并作为 LUAD 患者的预后指标。AFF4 通过加速糖酵解增强 LUAD 细胞的致瘤特性和顺铂耐药性。同时，糖酵解抑制恢复了 AFF4 过表达诱导的细胞增殖和迁移增加，并使过表达 AFF4 的 LUAD 细胞对顺铂敏感。机制上，AFF4 通过调节磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/雷帕霉素哺乳动物靶标（mTOR）信号通路促进糖酵解。AFF4 通过直接靶向其启动子下调磷酸酶和张力蛋白同源物（PTEN）的表达，激活 PI3K/AKT/mTOR 通路。此外，转录因子阴阳 1（YY1）通过结合其启动子上调 AFF4，进一步影响糖酵解和肿瘤发生。
AFF4 通过 PTEN 介导的 PI3K/AKT/mTOR 信号通路激活驱动代谢重编程、肿瘤进展和顺铂耐药，突出了抑制 AFF4 作为 LUAD 潜在治疗策略的重要性。
