Glycolytic Pfkp Acts as Lin41 Protein Kinase to Regulate Embryonic Stem Cell Differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA893540 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22019951_1.fastq.gz | Fastqsanger.gz | |||
| SRR22019951_2.fastq.gz | Fastqsanger.gz | |||
| SRR22019952_1.fastq.gz | Fastqsanger.gz | |||
| SRR22019952_2.fastq.gz | Fastqsanger.gz | |||
| SRR22019953_1.fastq.gz | Fastqsanger.gz |
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Project description:Yin Yang 1 (YY1) acts as a transcription factor crucially involved in cell proliferation, differentiation and survival. We here report that YY1, through gene expression regulation, plays an important role in prostate tumorigenesis, notably in castration-resistant prostate cancer (CRPC) models. Specifically, we found that YY1 displays a significantly elevated level among primary samples from prostate cancer patients, relative to normal. Depletion of YY1 in multiple independent prostate cancer model systems dramatically reduced tumor cell growth in vitro and significantly delayed oncogenic progression in vivo. Using integrated analyses of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq), we further defined YY1-regulated cistrome, among which include a set of metabolism-related genes such as PFKP (Phosphofructokinase, Platelet isoform), a rate-limiting enzyme essential for glycolysis. Via both gene loss-of-function and rescue studies, we demonstrate that PFKP serves as a key downstream direct target of YY1, significantly contributing to YY1-enforced oncogenic phenotypes such as enhanced tumor cell glycolysis and prostate cancer growth. Lastly, we show that BRD4, a cofactor of YY1, is critically involved in YY1-mediated activation of metabolic genes in prostate cancer cells. Altogether, this study unveils an oncogenic axis of YY1/BRD4-PFKP in prostate cancer for potentiating more aggressive tumor characteristics, which shall shed light on targeted therapy.
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Project description:Yin Yang 1 (YY1) acts as a transcription factor crucially involved in cell proliferation, differentiation and survival. We here report that YY1, through gene expression regulation, plays an important role in prostate tumorigenesis, notably in castration-resistant prostate cancer (CRPC) models. Specifically, we found that YY1 displays a significantly elevated level among primary samples from prostate cancer patients, relative to normal. Depletion of YY1 in multiple independent prostate cancer model systems dramatically reduced tumor cell growth in vitro and significantly delayed oncogenic progression in vivo. Using integrated analyses of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq), we further defined YY1-regulated cistrome, among which include a set of metabolism-related genes such as PFKP (Phosphofructokinase, Platelet isoform), a rate-limiting enzyme essential for glycolysis. Via both gene loss-of-function and rescue studies, we demonstrate that PFKP serves as a key downstream direct target of YY1, significantly contributing to YY1-enforced oncogenic phenotypes such as enhanced tumor cell glycolysis and prostate cancer growth. Lastly, we show that BRD4, a cofactor of YY1, is critically involved in YY1-mediated activation of metabolic genes in prostate cancer cells. Altogether, this study unveils an oncogenic axis of YY1/BRD4-PFKP in prostate cancer for potentiating more aggressive tumor characteristics, which shall shed light on targeted therapy.
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Project description:The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic ATP production, an event with consequences for both cell bioenergetics and cell fate. This response is regulated at the transcriptional level by HIF-1-dependent transcriptional upregulation of all ten glycolytic enzymes. However, this response alone does not account for the levels of ATP produced in hypoxia. Here, we investigated additional mechanisms of regulating glycolysis in hypoxia. We found that both intestinal epithelial cells treated with inhibitors of transcription and translation and human platelets (which lack nuclei) maintained the capacity for hypoxia-induced glycolysis, suggesting the involvement of a non-transcriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. Mass spectrometric analysis of the interactome of immunoprecipitated rate-limiting glycolytic enzymes identified hypoxia-sensitive complexes comprising multiple glycolytic enzymes and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of glycolytic complexes, though not dependent upon transcription, occurs via a HIF-1?-dependent mechanism, suggesting that HIF-1? may play a moonlighting role in the formation / maintenance of glycolytic complexes. Furthermore, we provide evidence for the presence of HIF-1? in cytosolic fractions of hypoxic cells which physically associated with the glucose transporter GLUT1 and the glycolytic enzyme PFKP in a hypoxia-sensitive manner. In conclusion, we hypothesize that HIF-1? plays a role in initiation and/or maintenance of glycolytic complexes in intestinal epithelial cells under hypoxic conditions in a manner which optimizes catalytic efficiency of the pathway by facilitating substrate channeling of glycolytic intermediates between sequential pathway enzymes. In hypoxia, cells undergo a metabolic switch to increased glycolysis. This has important implications for cell behavior, phenotype, and fate in both healthy and cancerous cells. Here we describe a mechanism by which HIF-1, in addition to increasing glycolytic enzyme expression, promotes glycolysis via the formation of a metabolic complex.
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Project description:The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic ATP production, an event with consequences for both cell bioenergetics and cell fate. This response is regulated at the transcriptional level by HIF-1-dependent transcriptional upregulation of all ten glycolytic enzymes. However, this response alone does not account for the levels of ATP produced in hypoxia. Here, we investigated additional mechanisms of regulating glycolysis in hypoxia. We found that both intestinal epithelial cells treated with inhibitors of transcription and translation and human platelets (which lack nuclei) maintained the capacity for hypoxia-induced glycolysis, suggesting the involvement of a non-transcriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. Mass spectrometric analysis of the interactome of immunoprecipitated rate-limiting glycolytic enzymes identified hypoxia-sensitive complexes comprising multiple glycolytic enzymes and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of glycolytic complexes, though not dependent upon transcription, occurs via a HIF-1?-dependent mechanism, suggesting that HIF-1? may play a moonlighting role in the formation / maintenance of glycolytic complexes. Furthermore, we provide evidence for the presence of HIF-1? in cytosolic fractions of hypoxic cells which physically associated with the glucose transporter GLUT1 and the glycolytic enzyme PFKP in a hypoxia-sensitive manner. In conclusion, we hypothesize that HIF-1? plays a role in initiation and/or maintenance of glycolytic complexes in intestinal epithelial cells under hypoxic conditions in a manner which optimizes catalytic efficiency of the pathway by facilitating substrate channeling of glycolytic intermediates between sequential pathway enzymes. In hypoxia, cells undergo a metabolic switch to increased glycolysis. This has important implications for cell behavior, phenotype, and fate in both healthy and cancerous cells. Here we describe a mechanism by which HIF-1, in addition to increasing glycolytic enzyme expression, promotes glycolysis via the formation of a metabolic complex.
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