PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1095427 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28527813_1.fastq.gz | Fastqsanger.gz | |||
| SRR28527813_2.fastq.gz | Fastqsanger.gz | |||
| SRR28527814_1.fastq.gz | Fastqsanger.gz | |||
| SRR28527814_2.fastq.gz | Fastqsanger.gz | |||
| SRR28527815_1.fastq.gz | Fastqsanger.gz |
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Project description:Glioblastoma is one of the most aggressive primary brain tumours in adults, with a dismal median overall survival of only 14 months after diagnosis1,2. Glioblastoma stem-like cells (GSCs), are particularly resistant to current therapies3,4, capable of self-renewal and tumour initiation5,6 and are hence thought to be major contributors to patient relapse. Glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is an essential gene for GSC survival, and is upregulated in these cells compared with in normal brain7. However, the mode of action of PFKFB4 in GSCs is unknown. Here we show a new role for PFKFB4 in the regulation of Hypoxia Inducible Factor 1 alpha (HIF1α) in GSCs. In a metabolic tracing study, we found that silencing PFKFB4 in GSCs resulted in a global downregulation of glucose metabolism. Gene expression profiling of PFKFB4-silenced GSCs revealed a downregulation of HIF1α target genes, and HIF1α protein levels are dramatically reduced in PFKFB4-silenced GSCs and other cancer cell lines. Finally, through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F box only protein 28 (FBXO28), as a new interaction partner of PFKFB4, which we show to regulate ubiquitylation and subsequent proteasomal degradation of HIF1α. Crucially, this newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF1α in a cancer specific manner. Compounds which disrupt the interaction between PFKFB4 and FBXO28 could be interesting therapeutic agents against glioblastoma and other cancer entities in which PFKFB4 regulates HIF1α stability.
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Project description:To explore the mechanisms by which PFKFB4 promotes breast cancer metastasis, we CRISPR-Cas knock-out PFKFB4 in two breast cancer lines for RNA-seq to identify downstream target genes that are regulated by PFKFB4
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Project description:Neuroinflammation is a pathological hallmark of several chronic neurological diseases, including multiple sclerosis (MS), and this process is driven by the sustained activation of myeloid cells. However, the pathogenic myeloid cells subset(s) and their regulation in MS remain unclear. Here, we identify a multiple sclerosis-associated microglia and macrophage (MSMM) subset defined as CD38+CD93+ that drives MS pathogenesis. MSMM exhibits pro-inflammatory and neurotoxic characteristics accompanied by aberrant activation of glycolysis. Mechanistically, we found that aberrant activation of glycolysis results in excessive lactate production and elevation of histone lactylation in MSMM. Histone lactylation (H3K18la and H4K12la) in turn activates the transcriptional modules of genes governing neuroinflammation and glycolysis, thereby promotes the formation of MSMM. Blockade of MSMM with anti-CD38 plus anti-CD93 neutralizing antibodies ameliorates neuroinflammation and MS-like pathologies in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inhibition of glycolysis through Ldha knock out or LDHA inhibitor decreases the number of MSMM and attenuates EAE severity. Together, these findings reveal a MS-associated pathogenic cell subset and provide potential therapeutic approaches for MS.
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Project description:In order to investigate the crucial role of PFKFB4 in glioblastoma stem-like cell (GSC) survival, gene expression microarray-based transcriptome analysis was conducted on GSCs transduced for 4 days with PFKFB4 shRNA compared with GSCs transduced with shNT.
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Project description:[Background & Aims] Histone lactylation is a lactate-dependent epigenetic modification driven by glycolysis. Although elevated histone lactylation has been reported in various cancer, the biological relevance of histone H4 lactylation in HCC remains unclear. This study aimed to investigate the clinicopathological relevance of H4K5 lactylation (H4K5la) and its role in regulating lactate metabolism to promote HCC progression. [Methods] The expression levels of H4K5la, H3K18la, and PanKla were evaluated in HCC tissues by immunohistochemistry. RNA-seq and ChIP-PCR analyses were performed on HCC cells treated with lactate to identify the downstream target genes mediated by H4K5la. Functional validation of these targets was conducted through knockdown and overexpression experiments, and biological effects were assessed both in vitro and in vivo. [Results] Elevated levels of H4K5la, H3K18la, and PanKla were associated with a poor prognosis, with H4K5la identified as an independent prognostic factor of overall survival. Upon lactate treatment, five genes including glycolytic enzyme ENO2 were consistently identified in three HCC cell lines, showing enrichment of H4K5la at their promoter regions. ENO2-KD reduced intracellular lactate and H4K5la levels, as well as in vivo tumorigenicity in HCC cells, while ENO2 overexpression exerted opposite functions. These findings establish a positive feedback loop: H4K5la increases ENO2 expression, which in turn amplifies glycolysis and lactate production, further elevating H4K5la. Moreover, ENO2 expression was tightly correlated with H4K5la levels in HCC tissues. [Conclusions] High H4K5la expression is an independent prognostic biomarker in HCC. H4K5la promotes HCC aggressiveness by enhancing glycolysis and tumor growth, forming a positive feedback loop with ENO2. Targeting this pathway may represent a promising therapeutic strategy for HCC.
2026-04-22 | GSE314771 | GEO
Project description:[Background & Aims] Histone lactylation is a lactate-dependent epigenetic modification driven by glycolysis. Although elevated histone lactylation has been reported in various cancer, the biological relevance of histone H4 lactylation in HCC remains unclear. This study aimed to investigate the clinicopathological relevance of H4K5 lactylation (H4K5la) and its role in regulating lactate metabolism to promote HCC progression. [Methods] The expression levels of H4K5la, H3K18la, and PanKla were evaluated in HCC tissues by immunohistochemistry. RNA-seq and ChIP-PCR analyses were performed on HCC cells treated with lactate to identify the downstream target genes mediated by H4K5la. Functional validation of these targets was conducted through knockdown and overexpression experiments, and biological effects were assessed both in vitro and in vivo. [Results] Elevated levels of H4K5la, H3K18la, and PanKla were associated with a poor prognosis, with H4K5la identified as an independent prognostic factor of overall survival. Upon lactate treatment, five genes including glycolytic enzyme ENO2 were consistently identified in three HCC cell lines, showing enrichment of H4K5la at their promoter regions. ENO2-KD reduced intracellular lactate and H4K5la levels, as well as in vivo tumorigenicity in HCC cells, while ENO2 overexpression exerted opposite functions. These findings establish a positive feedback loop: H4K5la increases ENO2 expression, which in turn amplifies glycolysis and lactate production, further elevating H4K5la. Moreover, ENO2 expression was tightly correlated with H4K5la levels in HCC tissues. [Conclusions] High H4K5la expression is an independent prognostic biomarker in HCC. H4K5la promotes HCC aggressiveness by enhancing glycolysis and tumor growth, forming a positive feedback loop with ENO2. Targeting this pathway may represent a promising therapeutic strategy for HCC.
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Project description:Radioresistance is a major cause of radiotherapy failure in lung cancer, and its mechanism has not been fully elucidated. Glucose metabolism is closely related to radioresistance, and targeting key molecules in glucose metabolism is expected to increase radiosensitivity. Our study demonstrated that the expression of the gluconeogenic enzyme PFKFB4 was upregulated in lung cancer. Genetic silencing and pharmacological inhibition of PFKFB4 significantly enhanced lung cancer radiosensitivity. Mechanistically, the fumaric acid/Rad51 axis is crucial for PFKFB4-induced radioresistance. PFKFB4 inhibits histone demethylase KDM1A by upregulating fumaric acid, which in turn increases the level of H3K4me1 at the Rad51 promoter region and induces Rad51 transcriptional activation, and ultimately leads to lung cancer radioresistance. Furthermore, by constructing a library of ubiquitinated compounds, the deubiquitinating enzyme USP10 was identified as a key upstream molecule for stabilizing PFKFB4 expression, and USP10 silencing downregulated fumaric acid and Rad51 in a PFKFB4-dependent manner, which in turn increased lung cancer radiosensitivity. In conclusion, the present study reveals that USP10-mediated PFKFB4deubiquitination promotes lung cancer radioresistance through activation of the fumaric acid/Rad51 axis and provides important evidence for the clinical translation of PFKFB4.
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