August 13, 2025Open Access

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

XYXufeng YaoTianjin University QCQian ChaiNanjing University of Chinese Medicine YMYuhao MaShandong University of Technology

Key Points

Overexpression of aff4 in lung adenocarcinoma cells leads to increased glycolysis and tumorigenic characteristics, along with cisplatin resistance.
Glycolysis inhibition effectively restores cell sensitivity to cisplatin in aff4-overexpressing lung adenocarcinoma cells, highlighting therapeutic potential.
Analysis using assays, western blotting, and bioinformatics demonstrated aff4's mechanism in modulating the pi3k/akt/mTOR signaling pathway.
Findings underscore the significance of aff4 as a prognostic indicator and potential therapeutic target in lung adenocarcinoma.

Abstract

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.

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