Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity
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ABSTRACT:
PROVIDER: PRJEB49656 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR7813970_1.fastq.gz | Fastqsanger.gz | |||
| ERR7813970_2.fastq.gz | Fastqsanger.gz | |||
| ERR7813980_1.fastq.gz | Fastqsanger.gz | |||
| ERR7813980_2.fastq.gz | Fastqsanger.gz | |||
| ERR7813971_1.fastq.gz | Fastqsanger.gz |
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Project description:Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies.
2022-12-31 | E-MTAB-11253 | biostudies-arrayexpress
Project description:Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction on solid cancers, by glucose transporter blocking or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are not known. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) cells induces de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (aKG), leading to attenuated activity of aKG-dependent histone demethylases and consequent histone hypermethylation. We further show that this de-differentiated and aggressive phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1a (HIF1a). Finally, we identified an HIF1a-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies targeting glucose uptake and glycolysis.
2023-04-12 | E-MTAB-11678 | biostudies-arrayexpress
Project description:Glucose deprivation promotes de-differentiation in lung adenocarcinoma
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Project description:Glucose deprivation induced gene expression
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Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. With a single LPS stimulation, Ezh2 null(Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.
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Project description:Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry (MS) analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. Interestingly, FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme which deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to Bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor Bortezomib response.
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Project description:Knockdown of YAP in HCT116 cells by lentivirus-mediated shRNA, and after glucose deprivation treatment using total RNA for sequencing analysis to evaluate the function of YAP in glucose deprivation induced gene expression.
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Project description:We investigated the function of the mTORC1 substrates and mRNA translation regulators 4EBP1/2 in the response to glucose deprivation. We uncovered that targeting 4EBP1/2 expression had a direct impact on the survival rates of cells challenged with glucose deprivation. To further define the mechanisms underlying 4EBP1/2 function under glucose deprivation, we conducted a proteomics analysis of HEK293 shRNA control and HEK293 shRNA 4EBP1/2 grown in basal media or under glucose deprivation (1 mM glucose containing media) for 30 hours.
2024-03-28 | PXD040931 | Pride
Project description:To assess the effect of sleep deprivation on glucose metabolism and elucidate the mechanism, we established the mouse model wth C57BL/6J that is useful for the intervention on sleep deprivation associated diabetes and evaluate the liver metabolism and gene expression. Single six hours sleep deprivation induced increased hepatic glucose production assessed by pyruvate tolerance test and the hepatic triglyceride content was significantly higher in the sleep deprivation group than freely sleeping control group. Liver metabolites such as ketone bodies were increased in sleep deprivation group. Some gene expressions which associated with lipogenesis were increased.
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