Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA264542 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Epigenetic and metabolic reprogrammings are implicated in cancer progression with unclear mechanisms. We report here that the histone methyltransferase NSD2 drives cancer cell and tumor resistance to therapeutics such as tamoxifen, doxorubicin, and radiation by reprogramming of glucose metabolism. NSD2 coordinately up-regulates expression of TIGAR, HK2 and G6PD and stimulates pentose phosphate pathway (PPP) production of NADPH for ROS reduction. We discover that elevated expression of TIGAR, previously characterized as a fructose-2,6-bisphosphatase, is localized in the nuclei of resistant tumor cells where it stimulates NSD2 expression and global H3K36me2 mark. Mechanistically, TIGAR interacts with the antioxidant regulator Nrf2 and facilitates chromatin assembly of Nrf2-H3K4me3 methylase MLL1 and elongating Pol-II, independent of its metabolic enzymatic activity. In human tumors, high levels of NSD2 correlate strongly with early recurrence and poor survival and are associated with nuclear-localized TIGAR. This study defines a nuclear TIGAR-mediated, epigenetic autoregulatory loop functioning in redox rebalance for resistance to tumor therapeutics. A total of 4 samples were analyzed in this study. The study included two cell lines, MCF7 and the tamoxifen-resistant subline TMR. Both were were cultured in medium containing vehicle control and/or 4-hydroxytamoxifen (Tam). The untreated MCF7 and TMR cell lines served as controls for the study.
2016-10-22 | E-GEOD-62613 | biostudies-arrayexpress
Project description:Epigenetic and metabolic reprogrammings are implicated in cancer progression with unclear mechanisms. We report here that the histone methyltransferase NSD2 drives cancer cell and tumor resistance to therapeutics such as tamoxifen, doxorubicin, and radiation by reprogramming of glucose metabolism. NSD2 coordinately up-regulates expression of TIGAR, HK2 and G6PD and stimulates pentose phosphate pathway (PPP) production of NADPH for ROS reduction. We discover that elevated expression of TIGAR, previously characterized as a fructose-2,6-bisphosphatase, is localized in the nuclei of resistant tumor cells where it stimulates NSD2 expression and global H3K36me2 mark. Mechanistically, TIGAR interacts with the antioxidant regulator Nrf2 and facilitates chromatin assembly of Nrf2-H3K4me3 methylase MLL1 and elongating Pol-II, independent of its metabolic enzymatic activity. In human tumors, high levels of NSD2 correlate strongly with early recurrence and poor survival and are associated with nuclear-localized TIGAR. This study defines a nuclear TIGAR-mediated, epigenetic autoregulatory loop functioning in redox rebalance for resistance to tumor therapeutics.
2016-10-22 | GSE62613 | GEO
Project description:Drug resistance is a major clinical challenge in achieving durable responses to targeted cancer therapeutics. Resistance mechanisms to new classes of epigenetic-targeted drugs entering the clinic remain largely unexplored. We used BET inhibition in MYCN-amplified neuroblastoma as a prototype to model innate and acquired resistance to chromatin remodeling inhibitors in cancer. Genome-scale, pooled lentiviral ORF and CRISPR knockout rescue screens nominated the PI3K pathway as a key signaling node that mediates resistance to BET inhibition.
2018-12-13 | GSE107706 | GEO
Project description:NRF2 integrates metabolic and epigenetic regulation in liver cancer
| PRJNA745335 | ENA
Project description:Drug resistance is a major clinical challenge in achieving durable responses to targeted cancer therapeutics. Resistance mechanisms to new classes of epigenetic-targeted drugs entering the clinic remain largely unexplored. We used BET inhibition in MYCN-amplified neuroblastoma as a prototype to model innate and acquired resistance to chromatin remodeling inhibitors in cancer. Genome-scale, pooled lentiviral ORF and CRISPR knockout rescue screens nominated the PI3K pathway as a key signaling node that mediates resistance to BET inhibition. RNA-seq profiling of BET inhibitor resistant cells revealed that global enhancer and super-enhancer remodeling leads to differential cell state commitment and the upregulation of receptor tyrosine kinases upstream of PI3K signaling, engendering a vulnerability to receptor tyrosine kinase (RTK) and PI3K inhibition. Large-scale, unbiased, chemical combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations with JQ1, a finding validated in vivo. These studies provide a comprehensive roadmap to elucidate resistance to epigenetic-targeted cancer therapeutics and inform efficacious combination therapies for second-generation clinical trials.
2018-12-13 | GSE107707 | GEO
Project description:This model is built by COPASI 4.24(Build 197), based on paper:
Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment.
Author:
James M. Greene, Jana L. Gevertz, Eduardo D. sontag
Abstract:
PURPOSE:Drug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols. MATERIALS AND METHODS:To better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance. RESULTS:Our model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment's propensity to induce resistance.
2024-09-02 | BIOMD0000000825 | BioModels
Project description:NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.
2020-06-24 | PXD015884 | Pride
Project description:Partitioning of cancer therapeutics in nuclear condensates
| PRJNA627353 | ENA
Project description:NRF2 Integrates Metabolic, Epigenetic and Oncogenic Regulation in Driving Liver Cancer Progression
| PRJNA761720 | ENA
Project description:The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. In disease, constitutive NRF2 activity promotes cancer progression while decreased NRF2 function contributes to neurodegenerative diseases. In contrast to the regulation of NRF2 protein stability in the cytoplasm, co-complexed proteins that govern NRF2 activity on chromatin are less clear. Using biotin proximity proteomics, we report networks for NRF2 and its family members NRF1, NRF3 and the NRF2 heterodimer MAFG. We found that the Parkinson’s disease zinc finger transcription factor ZNF746 (PARIS) physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 expression increased oxidative stress and apoptosis, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests that ZNF746 overexpression in Parkinson’s disease directly inhibits NRF2-driven neuroprotection.
2023-12-18 | PXD043248 | Pride