Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA218213 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pathway-based integrative analysis reveals a key role for the hexosamine biosynthetic pathway in castrate resistant prostate cancer with therapeutic implications
| PRJNA280214 | ENA
Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL
2015-04-03 | E-GEOD-67537 | biostudies-arrayexpress
Project description:Tumorigenesis is characterised by changes in transcriptional regulation and the androgen receptor (AR) has been identified as a key driver in prostate cancer. In this study, we show that the hexosamine biosynthetic pathway (HBP) genes are overexpressed in clinical prostate cancer and androgen-regulated in cell-lines. HBP senses metabolic status of the cell and produces an essential substrate for O-GlcNAc transferase (OGT), which regulates target proteins via glycosylation. Using immunohistochemistry, we found that OGT is up-regulated in the protein level in prostate cancer (n=1987) and its expression correlates with high Gleason Score, pT and pN stages and biochemical recurrence (for all, p<0.0001). Both a small molecule inhibitor and siRNAs targeting OGT decreased prostate cancer cell growth. Microarray profiling revealed that the principal effects of the OGT inhibitor in prostate cancer cells are on cell cycle progression and DNA replication. We identified MYC as a candidate upstream regulator of these genes and found that OGT inhibitor caused a dose-dependent loss of c-MYC protein but not mRNA in cell lines. Finally, we observed a statistically significant co-expression between c-MYC and OGT in human prostate cancer samples (n=1306, p=0.0012). Total RNA was extracted and experiment has three biological replicates for each condition, conditions are: 12 hours ST045849, 24 hours ST045849, 12 hours vehicle, 24 hours vehicle, 12 hours siOGT, 24 hours siOGT, 12 hours scrambled, 24 hours scrambled
2013-05-30 | E-GEOD-44624 | biostudies-arrayexpress
Project description:Tumorigenesis is characterised by changes in transcriptional regulation and the androgen receptor (AR) has been identified as a key driver in prostate cancer. In this study, we show that the hexosamine biosynthetic pathway (HBP) genes are overexpressed in clinical prostate cancer and androgen-regulated in cell-lines. HBP senses metabolic status of the cell and produces an essential substrate for O-GlcNAc transferase (OGT), which regulates target proteins via glycosylation. Using immunohistochemistry, we found that OGT is up-regulated in the protein level in prostate cancer (n=1987) and its expression correlates with high Gleason Score, pT and pN stages and biochemical recurrence (for all, p<0.0001). Both a small molecule inhibitor and siRNAs targeting OGT decreased prostate cancer cell growth. Microarray profiling revealed that the principal effects of the OGT inhibitor in prostate cancer cells are on cell cycle progression and DNA replication. We identified MYC as a candidate upstream regulator of these genes and found that OGT inhibitor caused a dose-dependent loss of c-MYC protein but not mRNA in cell lines. Finally, we observed a statistically significant co-expression between c-MYC and OGT in human prostate cancer samples (n=1306, p=0.0012).
2013-05-30 | GSE44624 | GEO
Project description:This study is to examine the role of RelA in regulation the activation of hexosamine biosynthetic pathway and N-glycosylation in RSV infection
2022-08-11 | PXD034013 | Pride
Project description:This study is to examine the role of IRE1-XBP1 in regulation the activation of hexosamine biosynthetic pathway and N-glycosylation of extracellular matrix in RSV infection
2022-10-14 | PXD034780 | Pride
Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells
2015-04-03 | GSE67537 | GEO
Project description:To better understand the biochemical changes associated with castrate resistant prostate cancer (CRPC), we developed a pathway-based integrated analytical method to examine prostate cancer (PCa) gene expression and metabolomic datasets and found distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) between androgen dependent (AD) PCa and CRPC, with elevated expression of HBP genes in primary PCa associated with poor clinical outcome. Expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in AD PCa while relatively diminished in CRPC.Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased aggressiveness, while GNPNAT1 knockdown decreased proliferation in AD PCa cells. Each scenario was accompanied by specific bio-energetic and molecular alterations. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine significantly enhanced efficacy of the anti-androgen enzalutamide in CRPC cells by repressing NF-Y driven cell cycle regulators. Our study demonstrates the therapeutic value of targeting altered metabolic pathways in lethal PCa.
2016-09-20 | GSE50661 | GEO
Project description:Glioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use nowadays. Although sugar metabolism through the hexosamine biosynthetic pathway (HBP) plays a key role in tumor aggressiveness and progression in different types of cancer, whether the HBP might be a targetable strategy for GBM is still lacking experimental evidence. Here we show that the HBP enzyme O-GlcNAcase (OGA) plays a critical role in GBM secretome signature. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered. Among these proteins, we observed that proteins related to proteasome activity and autophagy were consistently down-regulated in GBM cells upon OGA activity inhibition (iOGA). While the proteins IGFBP3 and HSPA5 were down regulated in iOGA GBM cells, the protein SQSTM1/p62 was a only identified in iOGA GBM cells. These in silico findings were in line with experimental evidence showing a decrease in autophagy in iOGA cells followed by a decrease in radio-resistance. Taken together our findings consistently bridge the protein profile in the secretome with functional evidence of autophagy regulation in GBM by the OGA activity. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.
2021-09-09 | PXD019496 | Pride
Project description:In order to define the role of the Hexosamine Biosynthetic Pathaway (HBP) in pancreatic cancer cells proliferation, survival and gemcitabine resistance, we treated MiaPaCa2 and BxPC3 cells with FR054, a novel HBP inhbitor, and gemcitabine either alone or in combination for 48h
2023-05-08 | GSE223303 | GEO