Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling [K RNAseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE224267 | GEO | 2023/02/08
REPOSITORIES: GEO
Similar Datasets
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
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE224270 | GEO
Project description:The dysregulation of the histone H3 lysine 36 (H3K36) methyltransferase, SETD2, is associated with worse clinical outcomes and metastasis in clear cell Renal Cell Carcinoma (ccRCC). Here, we reveal that kidney cancer cells displaying diminished H3K36me3 levels (SETD2 deficiency) show increased sensitivity to the anti-tumor effects of the DNA hypomethylating agent 5-aza-2’-deoxycytidine (Decitabine/DAC). DAC treatment induced stronger viral mimicry activation and immunostimulatory signals by higher transposable element (TE) expression in SETD2-mutant cancer cells. Surprisingly, we demonstrate that the increased TE abundance in SETD2-knockout (SETD2-KO) kidney cancer cells is substantially derived from mis-spliced products induced by DAC treatment. Epigenetic profiling suggests that differential DNA methylation, H3K36me3, and H3K9me3 marks across exons and intronic TEs might contribute to elevated mis-splicing rates specifically in the SETD2 loss context. Finally, SETD2 dysregulation also sensitized tumors in vivo to combinatorial therapy of DAC and immune checkpoint inhibitors highlighting the translational potential for this precision medicine.
2023-01-27 | GSE198673 | GEO
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.
2024-07-01 | GSE223688 | GEO
Project description:The dysregulation of the histone H3 lysine 36 (H3K36) methyltransferase, SETD2, is associated with worse clinical outcomes and metastasis in clear cell Renal Cell Carcinoma (ccRCC). Here, we reveal that kidney cancer cells displaying diminished H3K36me3 levels (SETD2 deficiency) show increased sensitivity to the anti-tumor effects of the DNA hypomethylating agent 5-aza-2’-deoxycytidine (Decitabine/DAC). DAC treatment induced stronger viral mimicry activation and immunostimulatory signals by higher transposable element (TE) expression in SETD2-mutant cancer cells. Surprisingly, we demonstrate that the increased TE abundance in SETD2-knockout (SETD2-KO) kidney cancer cells is substantially derived from mis-spliced products induced by DAC treatment. Epigenetic profiling suggests that differential DNA methylation, H3K36me3, and H3K9me3 marks across exons and intronic TEs might contribute to elevated mis-splicing rates specifically in the SETD2 loss context. Finally, SETD2 dysregulation also sensitized tumors in vivo to combinatorial therapy of DAC and immune checkpoint inhibitors highlighting the translational potential for this precision medicine.
2023-01-27 | GSE198670 | GEO
Project description:undifferentiated mouse skeletal muscle cells (myoblasts) and differentiated mouse skeletal muscle cells (myotubes) were subjected to treatment with siRNAs targeting SETD2 or a non-targeting siRNA (si-Ctrl). Differential gene expression analysis and splicing analysis was performed on the resulting data.
2022-06-03 | GSE199256 | GEO
Project description:Genome-wide DNA methylation profiling of SETD2-null 786-0 RCC cells treated with decitabine (100nM and 300nM) or DMSO vehicle. The Illumina Infinium HumanMethylation EPIC BeadChip was used to obtain DNA methylation profiles across approximately 850K CpGs.
2024-07-01 | GSE223697 | GEO
Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
2021-11-15 | GSE146540 | GEO
Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
2021-11-15 | GSE146537 | GEO
Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
2021-11-15 | GSE146539 | GEO