Frontiers in cell and developmental biology · 2026
NFYC upregulates KLF1 expression and activate LDHA to drive glycolysis and tumor growth in glioblastoma cells.
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Fang Yan, Yang Yanyan, Lv Zilu, Yan Jie, Li Pengfei, Ni Weimin
Аннотация
OBJECTIVE: Metabolic reprogramming is a hallmark of glioblastoma multiforme (GBM), with lactate dehydrogenase A (LDHA) playing a key role in aerobic glycolysis. However, the upstream transcriptional mechanisms driving LDHA overexpression in GBM remain poorly understood. This study aims to investigate the transcriptional regulatory network governing LDHA-mediated glycolysis and to explore the functional roles of KLF1 and NFYC in GBM progression.
METHODS: Bioinformatic analysis of The Cancer Genome Atlas data was performed to assess LDHA, KLF1, and NFYC expression in glioma. glioblastoma multiforme cell lines were used for loss- and gain-of-function studies by siRNA/shRNA knockdown and overexpression, including assessments of glycolytic flux, mitochondrial metabolism, cell proliferation, and apoptosis Metabolic activity was assessed using Seahorse extracellular flux analysis. Transcriptional regulation was evaluated by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Tumor growth was assessed in a subcutaneous xenograft model.
RESULTS: LDHA was significantly upregulated in GBM and associated with poor prognosis. LDHA knockdown suppressed tumor growth, glycolysis, mitochondrial respiration, and induced apoptosis. KLF1 was identified as a direct transcriptional activator of LDHA. NFYC was shown to bind the KLF1 promoter and positively regulate its expression. Functional studies demonstrated that the NFYC-KLF1-LDHA axis promotes GBM cell proliferation, inhibits apoptosis, and enhances glycolytic and mitochondrial metabolism. The oncogenic effects of NFYC were partially reversed by KLF1 knockdown, and vice versa.
CONCLUSION: This study reveals a novel hierarchical transcriptional pathway in which NFYC regulates KLF1, which in turn activates LDHA, driving aerobic glycolysis and tumor progression in GBM. Targeting the NFYC-KLF1-LDHA axis may represent a promising therapeutic strategy for glioblastoma.
METHODS: Bioinformatic analysis of The Cancer Genome Atlas data was performed to assess LDHA, KLF1, and NFYC expression in glioma. glioblastoma multiforme cell lines were used for loss- and gain-of-function studies by siRNA/shRNA knockdown and overexpression, including assessments of glycolytic flux, mitochondrial metabolism, cell proliferation, and apoptosis Metabolic activity was assessed using Seahorse extracellular flux analysis. Transcriptional regulation was evaluated by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Tumor growth was assessed in a subcutaneous xenograft model.
RESULTS: LDHA was significantly upregulated in GBM and associated with poor prognosis. LDHA knockdown suppressed tumor growth, glycolysis, mitochondrial respiration, and induced apoptosis. KLF1 was identified as a direct transcriptional activator of LDHA. NFYC was shown to bind the KLF1 promoter and positively regulate its expression. Functional studies demonstrated that the NFYC-KLF1-LDHA axis promotes GBM cell proliferation, inhibits apoptosis, and enhances glycolytic and mitochondrial metabolism. The oncogenic effects of NFYC were partially reversed by KLF1 knockdown, and vice versa.
CONCLUSION: This study reveals a novel hierarchical transcriptional pathway in which NFYC regulates KLF1, which in turn activates LDHA, driving aerobic glycolysis and tumor progression in GBM. Targeting the NFYC-KLF1-LDHA axis may represent a promising therapeutic strategy for glioblastoma.