Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE224270 | GEO | 2023/02/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.

Project description:SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.

| S-EPMC10006211 | biostudies-literature

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [KPY RNAseq]

Project description:RNA-sequencing analysis of murine KPY lung adenocarcinoma tumors in the presence and absence of Setd2. Tumors were harvested from KPY-Ctrl and KPY-SetdKO mice and were then subject to RNA-Seq to identify gene expression differences following loss of Setd2 expression.

2023-02-08 | GSE224269 | GEO

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [K RNAseq]

Project description:RNA-sequencing analysis of murine K lung adenocarcinoma tumors in the presence and absence of Setd2. Tumors were harvested from K-Ctrl and K-Setd2KO mice. Tumors were then subject to RNA-Seq to identify gene expression differences following loss of Setd2 expression.

2023-02-08 | GSE224267 | GEO

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

Project description:Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

| PRJNA930429 | ENA

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [K RNAseq]

Project description:Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [K RNAseq]

| PRJNA930434 | ENA

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [KPY RNAseq]

Project description:Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [KPY RNAseq]

| PRJNA930433 | ENA

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Project description:Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.

| S-EPMC4950506 | biostudies-literature

Systematic <i>In Vivo</i> Inactivation of Chromatin-Regulating Enzymes Identifies Setd2 as a Potent Tumor Suppressor in Lung Adenocarcinoma.

Project description:Chromatin-modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome-remodeling complex members Smarca4 (Brg1) or Arid1a had complex effects on lung adenocarcinoma initiation and progression. Loss of either Brg1 or Arid1a were selected against in early-stage tumors, but Brg1 loss continued to limit disease progression over time, whereas loss of Arid1a eventually promoted development of higher grade lesions. In contrast to these stage-specific effects, loss of the histone methyltransferase Setd2 had robust tumor-promoting consequences. Despite disparate impacts of Setd2 and Arid1a loss on tumor development, each resulted in a gene expression profile with significant overlap. Setd2 inactivation and subsequent loss of H3K36me3 led to the swift expansion and accelerated progression of both early- and late-stage tumors. However, Setd2 loss per se was insufficient to overcome a p53-regulated barrier to malignant progression, nor establish the prometastatic cellular states that stochastically evolve during lung adenocarcinoma progression. Our study uncovers differential and context-dependent effects of SWI/SNF complex member loss, identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma, and establishes model systems to facilitate further study of chromatin deregulation in lung cancer. Cancer Res; 77(7); 1719-29. ©2017 AACR.

| S-EPMC5380596 | biostudies-literature

Inhibition of mTORC1 signaling sensitizes hepatocellular carcinoma cells to glycolytic stress.

Project description:Reprogrammed glucose metabolism, especially glycolysis, is profoundly implicated in tumor development or metastasis. As the interconnectedness and flexibility of metabolic signaling, targeting a metabolic signaling molecule may have limited anti-tumor effects. Here, Gene set enrichment analysis (GSEA) was used to explore the accompanied effectors of glycolysis in hepatocellular carcinoma (HCC). Based on the expression of lactate dehydrogenase A (LDHA), a key enzyme in catalyzing pyruvate into lactate, the glycolytic ability of HCC was defined as low group and high group. GSEA of two independent GEO datasets showed that mTORC1 signaling was the most striking metabolic alternations in high group. Pharmacological inhibition of mTORC1 signaling with rapamycin decreased LDHA level and glycolytic capacity of six HCC cell lines. Furthermore, c-Myc was identified as a downstream target of mTORC1 signaling and mediated mTORC1-induced LDHA expression. Importantly, rapamycin sensitized HCC cells to the glycolysis inhibitor 2-deoxyglucose (2-DG) in vitro and in vivo. Meanwhile, genetic silencing several other downstream targets of mTORC1 signaling (TFEB, SREBP-1 and SKAR) failed to enhance or faintly influenced the cytotoxic effects of 2-DG. These results demonstrate that combining rapamycin with 2-DG holds significant promise as prospective clinical treatment in HCC.

| S-EPMC5088292 | biostudies-literature

SETD2 loss sensitizes cells to PI3K? and AKT inhibition.

Project description:Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3K?) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3K?-specific) and AZD8186 (PI3K?- and ?-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 ? and ? isoforms alone had modest (?) and no (?) effect on ccRCC cell viability, growth, and migration. In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3K? causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3K?-specific inhibitors in ccRCC.

| S-EPMC6363018 | biostudies-literature

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