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

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

PROVIDER: PRJNA930429 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23305237_1.fastq.gz	Fastqsanger.gz
	SRR23305237_2.fastq.gz	Fastqsanger.gz
	SRR23305238_1.fastq.gz	Fastqsanger.gz
	SRR23305238_2.fastq.gz	Fastqsanger.gz
	SRR23305239_1.fastq.gz	Fastqsanger.gz

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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]

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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]

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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 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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-08 | GSE224270 | GEO

SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

Project description:SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

Project description:Large-scale sequencing efforts in Clear cell renal cell carcinoma (ccRCC) have found a high prevalence of mutations in chromatin-related genes. Prominent within this group is SETD2, which is mutated in 15% of ccRCC and is associated with aggressive disease. SETD2 is a methyltransferase responsible for trimethylating lysine 36 on histone H3 (H3K36me3). Although it is not completely understood how SETD2 loss contributes to ccRCC tumorigenesis, it is thought that it reprograms the epigenetic landscape of the cell. Here we explore the impact that SETD2/H3K36me3 loss has on the DNA methylome in ccRCC cells. DNA methylation was measured using the EPIC DNA methylation assay in 786-O ccRCC cells and non-cancerous transformed proximal tubule kidney cells (HKC) with and without SETD2. Sensitivity to DNA hypomethylating agents was assessed by dose-response assay using 5-aza-2'-deoxycytidine. Apoptosis was measured via Annexin-V/PI staining by flow cytometry. Mitochondrial fitness was evaluated by electron microscopy and flow cytometry. Moreover, activity of 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, in was assessed in SETD2 WT/KO xenografts in NOD-Scid mice. SETD2 loss resulted in DNA hypermethylation in HKC cells and to a greater extent in 786-O. Dose-response assays showed that SETD2-null ccRCC cells are sensitive to 5-aza-2'-deoxycytidine. Furthermore, Annexin-V/PI staining revealed more apoptotic and necrotic cells in SETD2-null cells following 5-aza-2'-deoxycytidine treatment, which was rescued using a Caspase inhibitor. In addition, 5-aza-2'-deoxycytidine induced profound changes in mitochondria in SETD2-null cells, including loss of membrane potential and size reduction. Indeed, in vivo experiments verified increased SETD2-null xenografts’ sensitivity to 5-aza-2'-deoxycytidine. We show that SETD2 loss in ccRCC cells causes DNA hypermethylation, creating a synthetic lethal dependency with DNA hypomethylating agents.

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RNA mis-splicing sensitizes SETD2-mutant kidney cancer cells to DNMTi

Project description:RNA mis-splicing sensitizes SETD2-mutant kidney cancer cells to DNMTi

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents [methylation]

Project description:SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents [methylation]

| PRJNA927301 | ENA