Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

KDM6A(UTX) is an epigenetic gatekeeper of mTORC1 signalling in cancer

ABSTRACT: Large-scale genome sequencing efforts of human tumors identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumor development and progression is largely unknown. Here, we identify the histone demethylase KDM6A as an important tumor suppressor in solid cancers, such as liver cancer and pancreatic cancer. KDM6A-deficient tumors show hyperactivation of mTORC1 signaling, whereas endogenous KDM6A re-expression in established KDM6A-deficient tumors diminishes mTORC1 activity by fostering the expression of crucial negative pathway regulators, such as DEPTOR, TSC1, and TSC2, resulting in tumor regression. Importantly, KDM6A expression in human tumors correlates with mTORC1 activity and KDM6A-deficient tumors exhibit increased sensitivity to mTORC1 inhibition. Hence, our results link KDM6A-dependent epigenetic remodeling to mTORC1 signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE155630 | GEO | 2022/07/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

KDM6A(UTX) is an epigenetic gatekeeper of mTORC1 signalling in cancer

Project description:KDM6A(UTX) is an epigenetic gatekeeper of mTORC1 signalling in cancer

| PRJNA650533 | ENA

Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).

2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress

Rapamycin effect on Wild Type and TSC deficient Mouse Embryonic Fibroblasts : Time Course

Project description:Aberrant activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a common molecular event in a large variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell intrinsic consequences of mTORC1 activation remain poorly defined. Here, we identify global trancriptional changes in TSC1 and TSC2 null MEFs, which exhibit constitutive activation of mTORC1, compared to wild-type littermate control lines. A rapamycin time course is included to determine those changes that are dependent on mTORC1 signaling, revealing mTORC1 induced and repressed transcripts. In order to identify mTORC1-dependent transcriptional changes, we compared wild-type MEFs to both Tsc1-/- and Tsc2-/- MEFs following serum starvation, where mTORC1 signaling is off in wild-type cells and fully active in TSC-deficient cells. All cell lines were serum-starved for 24 h, and the Tsc1-/- and Tsc2-/- cells were treated with a time course of rapamycin prior to the isolation of mRNA for microarray analysis. Immortalized wild-type (Tsc2+/+ p53-/-), Tsc1-/- (p53+/+, 3T3-immortalized), and Tsc2-/- (p53-/-, derived from a littermate of the wild-type cell line) MEFs are the three cell lines used in this study and were derived in the laboratory of David J. Kwiatkowski (Brigham and Women's Hospital, Harvard Medical School, Boston, MA). Wild-type and null MEFs were grown to 70% confluence in 10 cm plates and were serum starved for 24 h in the presence of vehicle (DMSO) for 24 h or rapamycin (20 nM) for 2, 6, 12, or 24 h. All vehicle-treated samples (0 h time points) were plated in triplicate and all rapamycin time course samples were plated in duplicate. For each replicate, expression analysis was performed by hybridization to an Affymetrix Mouse 430_2 oligonucleotide microarray chip.

2010-07-30 | E-GEOD-21755 | biostudies-arrayexpress

Rapamycin effect on Wild Type and TSC deficient Mouse Embryonic Fibroblasts : Time Course

2010-07-30 | GSE21755 | GEO

Silencing of KDM6A regulates TGF-β signaling pathway in MCF10A cells

Project description:Massive parallel sequencing projects identified KDM6A as a tumor suppressor gene with recurrent loss-of-function mutations multiple cancers. However, in breast cancer, reports on the functional role of KDM6A is paradoxical or even puzzling, suggesting the role of KDM6A may be context dependent. We sought to investigate the functional role of KDM6A in triple negative breast cancer with using MCF10A cells.

2022-05-23 | GSE131701 | GEO

Peli1-mediated TSC1 ubiquitination site

Project description:Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wildtype T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as an important regulator of T cell metabolism and antitumor immunity and suggest a novel mechanism that controls mTORC1 activation.

2020-11-23 | PXD020734 | Pride

Truncated KDM6A exhibits differential chromatin occupancy and regulatory interactions

Project description:Genome-wide studies characterizing mutational landscape of bladder cancer revealed the exceptionally high rate of chromatin modifier genes in bladder cancer. Thus, epigenetic deregulation is a critical theme which needs further investigation for bladder cancer research. One of the highly mutated genes in bladder cancer is KDM6A, functioning as H3K27 demethylase and part of MLL3/4 complexes. To decipher the role of KDM6A in normal vs tumor setting, we identified the genomic localization profiles of KDM6A in normal, immortalized and cancer bladder cells. Our results showed differential occupancy of KDM6A at the genes involved in cell differentiation, chromatin organization and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed an enrichment for HES1 for the KDM6A peaks identified for T24 bladder cancer cell line, which has a truncating mutation in KDM6A and lacking demethylase domain and also for the other clusters showing KDM6A localization. For the first time, using co-immunoprecipitation experiments, we show that KDM6A is in complex with TLE co-repressors and HES1, and illustrate the potential interaction of KDM6A with TLE co-repressors, HES1, RUNX, HHEX transcription factors by computational structural biology models. Our work makes important contributions to the understanding of KDM6A malfunction in bladder cancer and provides models for the functioning of KDM6A independent of its demethylase activity.

2023-03-03 | GSE216625 | GEO

KDM6A loss recruits tumor-associated neutrophils and promotes neutrophil extracellular trap formation via the CXCL1-CXCR2 axis in pancreatic cancer

Project description:Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, how KDM6A loss impacts PDAC tumor immune microenvironment is not known. Tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) in the tumor microenvironment contribute to PDAC progression. This study used genetically engineered pancreas-specific Kdm6a-knockout PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased TANs and NETs formation. Genome-wide Bru-seq analysis showed that the expression of many chemotactic cytokines, especially CXC motif chemokine ligand 1 (CXCL1), were upregulated in KDM6A-knockout PDAC cells. We confirmed that KDM6A-deficient PDAC cells secreted higher levels of CXCL1 protein, which in turn recruits neutrophils. Furthermore, the CXCL1 neutralizing antibody blocked the chemotactic and NETs-promoting property of KDM6A-deficient PDAC cells and tumor growth in a syngeneic orthotopic xenograft mouse model, confirming that CXCL1 was the main mediator of chemotaxis and PDAC growth in this model. These findings shed light on how KDM6A regulates tumor immune microenvironment and PDAC progression and suggest that the CXCL1-CXCR2 axis may be a candidate target for treating PDACs with KDM6A loss.

2022-11-23 | GSE202873 | GEO

Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

2011-07-12 | GSE29797 | GEO

RNA-seq analysis of Kdm6a deficient brains in mice

Project description:Kdm6a is an X-linked histone demethylase that activates gene expression via removal of the repressive methylation mark at histone H3 lysine 27 (H3K27). In humans, KDM6A mutations cause Kabuki syndrome, a disorder characterized by intellectual disability and motor coordination deficits. To assess the role of Kdm6a in brain development and behavior, we generated a neuron-specific Kdm6a deficient mouse model using Cre-LoxP recombination. The mutant mice exhibited an adult-onset deficit in motor coordination. We then performed RNA-seq analysis to determine the mis-regulated genes that are listed in this dataset.

2017-05-06 | GSE81251 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data