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Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2 [C4-2_siEZH2]

ABSTRACT: It is well established that EZH2, a lysine methyltransferase, is upregulated in most of aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belongs to the HMG-CoA synthase, in prostate and breast cancers. Furthermore, HMGCS2 is inversely related to cancer progression and prognosis in these cancers and is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction -mediated protein degradation. More importantly, ketone drink of BHB administration dramatically reduces tumor size and weight in a prostate cancer xenograft model. Combining ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, EZH2- HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer and ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269259 | GEO | 2025/05/27

REPOSITORIES: GEO

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Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2

Project description:It is well established that EZH2, a lysine methyltransferase, is upregulated in most of aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belongs to the HMG-CoA synthase, in prostate and breast cancers. Furthermore, HMGCS2 is inversely related to cancer progression and prognosis in these cancers and is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction -mediated protein degradation. More importantly, ketone drink of BHB administration dramatically reduces tumor size and weight in a prostate cancer xenograft model. Combining ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, EZH2- HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer and ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.

2025-05-27 | GSE269208 | GEO

Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2

Project description:Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2

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Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2 [C4-2_siEZH2]

Project description:Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2 [C4-2_siEZH2]

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β-hydroxybutyrate restores T cell metabolism and function in severe COVID-19

Project description:Anorexia and fasting are host adaptations to acute infection, inducing a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB). However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). BHB promotes the survival and the production of Interferon-g from CD4+ T cells. Using metabolic tracing analysis, we uncovered that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we find that ketogenic diet (KD) reduced pulmonary fibrosis, a feature particular pronounced in COVID-19 ARDS and delivery of BHB as ketone ester drink reduces the mortality of SARS-CoV-2 infected mice. Altogether, our data suggest that impaired ketogenesis in patients with SARS-CoV-2 infection accounts, at least partially for disease progression and that supplementation ketone ester might represent an easy-to-implement treatment to improve the clinical outcome of COVID-19 patients.

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Impaired ketogenesis in Leydig Cells drives testicular aging

Project description:Testicular aging commonly leads to testosterone deficiency and impaired spermatogenesis, yet the underlying mechanisms remain elusive. Here, a comprehensive analysis of senescence landscapes in mice testes during aging revealed that the Leydig cells (LCs) are particularly vulnerable to aging processes. Single-cell RNA sequencing identified the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme of ketogenesis, decreased significantly in LCs from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid (BHB) and acetoacetic acid (AcAc) in the young testes were substantially higher than that in serum, but significantly diminished in aged testes. Silencing of Hmgcs2 in young LCs resulted in decreased ketone body production, which in turn drove LCs senescence and accelerated testicular aging. Mechanistically, BHB acted as an endogenous inhibitor of histone deacetylase 1 to upregulate the expression of Foxo3a by promoting histone acetylation, thereby mitigating LCs senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral BHB supplementation alleviated LCs senescence and ameliorated testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting novel therapeutic avenues for addressing age-related testicular dysfunction.

2025-03-27 | GSE287203 | GEO

TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression

Project description:This SuperSeries is composed of the following subset Series: GSE28948: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression data) GSE28950: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (ChIP-Seq data) GSE35540: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression after ERG KD) Refer to individual Series

2012-04-26 | E-GEOD-28951 | biostudies-arrayexpress

TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression data)

Project description:Deregulation of the Androgen Receptor (AR) transcriptional network is a common hallmark in prostate cancers. To achieve its precise transcriptional role, AR needs to co-operate specifically with a plethora of cofactors. In prostate cancers, AR transcription collaborators are frequently aberrantly over-expressed, altering the AR signaling pathway to one that promotes oncogenesis. Recently, the prostate cancer recurrent fusion gene, ERG, was shown to promote tumor progression by acting as a repressor of AR signaling. However, the exact mechanics and the functional consequences associated with this crosstalk between ERG and AR still remains relatively unknown. Interestingly, through chromatin immunoprecipitation coupled with massively parallel sequencing, we discover that ERG and other commonly over-expressed transcriptional co-repressors (HDAC1, HDAC2, HDAC3 and EZH2) are wired into an AR-centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. We show that ERG represses several AR target genes involved in epithelial differentiation. Furthermore, we demonstrated that suppression of the androgen-induced gene, Vinculin, by ERG and histone deacetylases increases cancer cell invasiveness. From our results, we propose that ERG, histone deactelyases and the histone methyltransferase, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, in part through modulating the transcriptional output of AR. Gene expression profiling of human prostate cancer VCaP cells with time-course dihydrotestosterone (DHT) stimulation using microarrays. Triplicates were generated for each treatment/time point.

2012-04-26 | E-GEOD-28948 | biostudies-arrayexpress

TMPRSS2-ERG, HDACs and EZH2 are involved in an AR centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression after ERG KD)

Project description:Deregulation of the Androgen Receptor (AR) transcriptional network is a common hallmark in prostate cancers. To achieve its precise transcriptional role, AR needs to co-operate specifically with a plethora of cofactors. In prostate cancers, AR transcription collaborators are frequently aberrantly over-expressed, altering the AR signaling pathway to one that promotes oncogenesis. Recently, the prostate cancer recurrent fusion gene, ERG, was shown to promote tumor progression by acting as a repressor of AR signaling. However, the exact mechanics and the functional consequences associated with this crosstalk between ERG and AR still remains relatively unknown. Interestingly, through chromatin immunoprecipitation coupled with massively parallel sequencing, we discover that ERG and other commonly over-expressed transcriptional co-repressors (HDAC1, HDAC2, HDAC3 and EZH2) are wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. We show that ERG represses several AR target genes involved in epithelial differentiation. Furthermore, we demonstrated that suppression of the androgen induced gene, Vinculin, by ERG and histone deacetylases increases cancer cell invasiveness. From our results, we propose that ERG, histone deactelyases and the histone methyltransferase, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, in part through modulating the transcriptional output of AR. Gene expression profiling of human prostate cancer VCaP cells with time course DHT stimulation using microarray.

2012-04-26 | E-GEOD-35540 | biostudies-arrayexpress

TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (ChIP-Seq data)

Project description:Deregulation of the Androgen Receptor (AR) transcriptional network is a common hallmark in prostate cancers. To achieve its precise transcriptional role, AR needs to co-operate specifically with a plethora of cofactors. In prostate cancers, AR transcription collaborators are frequently aberrantly over-expressed, altering the AR signaling pathway to one that promotes oncogenesis. Recently, the prostate cancer recurrent fusion gene, ERG, was shown to promote tumor progression by acting as a repressor of AR signaling. However, the exact mechanics and the functional consequences associated with this crosstalk between ERG and AR still remains relatively unknown. Interestingly, through chromatin immunoprecipitation coupled with massively parallel sequencing, we discover that ERG and other commonly over-expressed transcriptional co-repressors (HDAC1, HDAC2, HDAC3 and EZH2) are wired into an AR-centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. We show that ERG represses several AR target genes involved in epithelial differentiation. Furthermore, we demonstrated that suppression of the androgen-induced gene, Vinculin, by ERG and histone deacetylases increases cancer cell invasiveness. From our results, we propose that ERG, histone deactelyases and the histone methyltransferase, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, in part through modulating the transcriptional output of AR. Genome-wide binding analysis of AR, ERG, HDAC1, HDAC2, HDAC3 and EZH2 in VCaP with and without DHT (dihydrotestosterone) stimulation using ChIP-Seq. 15 samples including 1 control (input).

2012-04-26 | E-GEOD-28950 | biostudies-arrayexpress

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Project description:To investigate the role of ketone body in the transcriptome in neonatal mouse heart, we constructed Hmgcs2 knockout mice and performed gene expression profiling analysis using data obtained from RNA-seq of wild-type and Hmgcs2 knockout mouse hearts at postnatal 3rd day.

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