GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193249 | GEO | 2022/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT
| PRJNA795484 | ENA
Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4. Liver tissue samples were collected from hepatocyte- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice after fasting (22 h) or refeeding (4 h). Gene expression was analyzed by microarray. Mice were on a mixed background of C57BL/6J and 129.
2014-08-20 | E-GEOD-60527 | biostudies-arrayexpress
Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4.
2014-08-20 | GSE60527 | GEO
Project description:The cellular heterogeneity within a tumor can be determined by core genetic and epigenetic programs that operate in certain cells (tumor initiating cells – TICs), providing them with the degree of plasticity needed for induction of metastasis and resistance to therapy. Here we show that the metabolic enzyme nicotinamide N-methyl transferase (NNMT) promotes TIC plasticity in Estrogen Receptor (ER) alpha negative breast cancer. NNMT downregulation delays tumor formation and its full depletion impairs metastasis formation in mice. Mechanistically, NNMT loss increases deposition of H3K9-me2/3 and H3K27-me3 at the promoter of genes involved in stem cell regulation, shutting down their expression and upregulating luminal differentiation genes. This study reveals a major function of NNMT in maintaining core epigenetic programmes that promote TIC self-renewal and metastasis and that repress luminal differentiation.
2023-04-13 | GSE114875 | GEO
Project description:Analysis of gene expression in human CAFs with control (shCtrl) or shRNA against NNMT (shNNMT) expression or normal fibroblasts expressing control (Ctrl) or NNMT overexpression (NNMT) constructs. Cells were infected with lentivirus to express the indicated shRNA construct. Hypothesis is that knockdown of NNMT will affect expression of genes via regulation of histone methylation status.
2019-05-01 | GSE112497 | GEO
Project description:High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. We developed a label- free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene- expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.
2019-04-18 | PXD006396 | Pride
Project description:H3K9me3, H3K27me3, H3K27ac and H3K4me3 ChIP-sequencing in SUM159PT NNMT-WT, NNMT-KOd and NNMT KOs breast cancer cells.
| PRJNA472964 | ENA
Project description:Microalgal lipid, a feasible substrate for biofuel, is typically accumulated during the stationary growth phase. Generating strains which trigger lipogenesis from the exponential growth phase will enhance lipid productivity, reduce cost of biofuel production. We characterized a lipid-rich microalgal mutant, Dunaliella tertiolecta, which exhibited a six-fold enhancement of neutral lipids production in the exponential growth phase with marginal compromise on growth (4%). Using transcriptomics and metabolomics, regulatory mechanisms of the mutant were uncovered.
2016-10-24 | GSE82121 | GEO
Project description:High grade serous carcinoma (HGSC) arising from either the fallopian tube or ovary has a poor prognosis primarily due to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer (OvCa)1,2, but a systematic examination of both the tumor and stromal compartments is critical to understanding OvCa metastasis. We developed a label-free proteomic workflow to analyze as few as 5,000 formalin-fixed, paraffin embedded cells microdissected from each compartment. The tumor proteome was comparatively stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and the proteins it regulates. Stromal NNMT expression was necessary and sufficient for several functional aspects of the cancer associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT supported OvCa migration, proliferation, and in vivo growth and metastasis. Expression of NNMT in CAFs led to a depletion of S-adenosyl methionine (SAM) and a reduction in histone methylation associated with extensive gene expression changes in the tumor stroma. This work supports the use of ultra-low input proteomics to identify candidate drivers of disease phenotypes and reveals that NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma and a novel treatment target.
2019-05-01 | GSE124014 | GEO
Project description:The most common subset of renal carcinoma, clear cell renal cell carcinoma (ccRCC), is characterized by accentuated accumulation of neutral lipids in lipid droplets and adipogenic trans-differentiation. Because obesity is a major risk factor in the development of ccRCC, we investigated the role of the adipokines in driving lipid metabolism and tumorigenesis in ccRCC. Through in silico screening, we identified the adipokine chemerin as candidate pro-oncogenic factor that is overexpressed in tumors and prognostic for patient outcome. Both ccRCC patient tumor tissues and serum exhibit elevated chemerin levels as compared to normal controls in an obesity-dependent manner. Attenuation of chemerin by several approaches in ccRCC cells led to significant impairments of tumor growth in both in vitro and in vivo models. A multi-omic approach revealed that chemerin suppresses fatty acid oxidation and maintains fatty acid levels which feed into transcriptional activation of hypoxia-inducible factor 2 (HIF2) expression. Suppression of chemerin therefore induced excess fatty acid oxidation and led to ferroptosis. CoQ and mitochondrial complex IV, derived mainly from lipid, were affected after chemerin inhibition, contributing to mitochondrial dysfunction and lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage, increased cell death, and diminished tumor growth, strengthening the translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology.
2021-08-11 | GSE159716 | GEO