Energy stress-induced lncRNA GIRGL modulates glucose metabolism reprogramming through upregulating MCT4 by interacting with YBX1 in lung adenocarcinoma

Metabolic reprogramming stands as a pivotal hallmark of cancer, enabling cancer cells to undergo adaptive metabolic alterations that sustain their survival and proliferation under energy stress conditions. The specific function of lncRNAs in cancer cells within the nutrient-deprived tumor microenvironment remains largely uncharacterized. The aim of this study is to investigate the role of energy stress-induced lncRNA GIRGL in glucose metabolism reprogramming in LUAD cells. Reduced glucose concentrations were employed to simulate the energy-stress conditions in cancer cells. Locked nucleic acid antisense oligonucleotides (LNA-ASOs) were designed to knockdown the expression of GIRGL in LUAD cells. The oncogenic role of GIRGL in LUAD cells was determined by cell proliferation, migration and invasion assays. Effect of GIRGL on glucose metabolism reprogramming was measured by detecting glucose uptake, lactate secretion, pyruvate production and Seahorse analysis. Fluorescence in situ hybridization (FISH) was conducted to examine the location of GIRGL in LUAD cells. Xenograft mouse model and 18 F-FDG micro-PET/CT were used to study the role of GIRGL in vivo. Chromatin Immunoprecipitation (ChIP), RNA‑pulldown, RNA immunoprecipitation (RIP) assays were utilized to elucidate the underlying molecular mechanisms of GIRGL. GIRGL was upregulated in LUAD tissues and correlated with clinical characteristics and tumor glucose uptake in LUAD patients. High GIRGL expression was associated with poor overall survival in univariate analysis, although multivariable analysis did not reach statistical significance. Energy stress induced expression of GIRGL via AMPK/FOXO3 axis, and GIRGL promoted glucose metabolism reprogramming and cancer progression of LUAD cells via MCT4, a primary mediator for the transmembrane transport of lactate in glycolysis. Mechanistically, GIRGL interacted with transcription factor YBX1 and activated YBX1-mediated transcription of MCT4. Collectively, these findings indicated that GIRGL played a pivotal role in regulating metabolic adaptation in LUAD cells, further implicating it as a promising prognostic biomarker requiring further validation.