AFF4 promotes tumor progression and cisplatin resistance by modulating the PTEN/PI3K/AKT/mTOR axis to accelerate glycolysis in lung adenocarcinoma

作者：Xufeng Yao, Qian Chai, Yuhao Ma, Guomeng Li, Tiantian Jia, Xiaohang Zhang, Tao Xia, Xiaozheng Wei, Xueyi Feng, Yanke Zhang, Yaqian Zhang, Xueqin Wang, Danye Han, Zongwei Li, Lei Zhao, Qian Dai · 发表于：Cell & Bioscience · 年份：2025 · DOI：10.1186/s13578-025-01455-1 · 被引用次数：9 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Microtubule and mitosis dynamics、RNA Research and Splicing

BACKGROUND: 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. METHODS: 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. RESULTS: 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 m...