Dysregulated lipid metabolism blunts the sensitivity of B16F10 melanoma cells to EZH2 inhibitor
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ABSTRACT:
PROVIDER: PRJNA684616 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13243607_1.fastq.gz | Fastqsanger.gz | |||
| SRR13243607_2.fastq.gz | Fastqsanger.gz | |||
| SRR13243608_1.fastq.gz | Fastqsanger.gz | |||
| SRR13243608_2.fastq.gz | Fastqsanger.gz | |||
| SRR13243609_1.fastq.gz | Fastqsanger.gz |
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Project description:The sensitivity has been the key issue for EZH2 inhibitor in cancer therapy. Although it has been approved by Food and Drug Administration (FDA) in 2020, the relative narrow scope still limits its clinical application. In this study, we utilized B16F10 melanoma cell line which is resistant to EZH2 inhibitor GSK126 to an extent to investigate the underlying mechanism. We found that although the proliferative phenotype didn't show any difference upon treatment with GSK126 at 10 μM, the transcriptome and metabolome changed profoundly. Gene set enrichment analysis and metabolites pathway enrichment analysis revealed that GSK126 induced broad shifts in glucose, amino acids and lipid metabolism. Lipid synthesis were strengthened with elevated abundance of unsaturated fatty acids. We also found attenuated tricarboxylic acid cycle metabolism, and decreased amino acids levels. The liver lipid accumulation and the increased blood triglycerides level after GSK126 treatment were further confirmed in a mouse model. Indeed, the combination of GSK126 and lipolysis agent fenofibrate significantly attenuated the proliferation of B16F10 and increased the sensitivity to GSK126. Therefore, the dysregulated lipid metabolism blunts the sensitivity of B16F10 to GSK126. This study uncovered the iceberg under the sea and identified the Achilles heel of EZH2 inhibitor, so that it provides the novel strategy for further combination therapy.
2022-02-23 | GSE163078 | GEO
Project description:BackgroundSensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism.MethodsIncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively.FindingsWe found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids.InterpretationDysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance.FundingNational Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).
| S-EPMC8850333 | biostudies-literature
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:The Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is an essential epigenetic modifier able to methylate lysine 27 on histone H3 (H3K27) to induce chromatin compaction, protein complex recruitment and ultimately transcriptional repression. Hematologic malignancies, including Diffuse Large B cell lymphoma (DLBCL) and Acute myeloid leukemia (AML) have shown a high EZH2-mutation frequency (>20%) associated with poor clinical outcomes. Particularly, two distinct oncogenic mutations, so-called gain-of-function (Y641F and A677G) and loss-of-function (H689A and F667I) are found in the catalytic domain of EZH2. In this study, a comprehensive multi-omics approach was employed to characterize downstream effects of H3K27me3 deposition driven by EZH2 mutations. Human embryonic kidney cells (HEK293T) were transfected to generate three stable EZH2 mutants: EZH2(Y641F), EZH2(A677G), and EZH2(H689A/F667I), which were validated via immunoblotting and DIA-MS-based histone profiling assay. Subsequently, constructs were analyzed under a comprehensive multi-omics approach including label-free whole-cell proteomics, acquired with a Bruker timsTOF Pro HPLC-MS/MS with Ion Mobility. Important protein interactors at nuclear level were dysregulated, such as SMYD3 (SET and MYND domain containing 3), NSD2 (nuclear receptor binding SET domain protein 2) and CHD7 (chromodomain helicase DNA binding protein 7), suggesting a cooperative network of chromatin remodelers for gene expression reprogramming.
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Project description:BMP2 treatment significantly reduces growth of B16F10 melanoma spheroids. This experiment analyses the transcriptome changes in B16F10 cells treated with or without BMP2.
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Project description:We have isolated cells from the B16F10 melanoma cell line which express the vascular-selective marker PECAM1 Here we used microarrays to determine expression profile differences across the mouse genome to determine whether these cells display additional endothelial characteristics PECAM1+ and PECAM1- B16F10 clones, along with mouse endothelial cells were cultured and harvested for RNA, which was then used in an Affymetrix Mouse Gene 1.0 ST array to determine expression signatures
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Project description:Resistance to tamoxifen is a major challenge in the treatment of estrogen receptor positive breast cancer. Acquired resistance to drug involves multilayered genetic and epigenetic regulation . The oncogene EZH2 plays significant role in the development of resistance against tamoxifen, widely used in the treatment of breast cancer. Inhibition of EZH2 has proven to reverse the tamoxifen resistance breast cancer cells back to the sensitive state. The molecular mechanism through which EZH2 inhibition triggers its effects are not known.This study was conducted to understand the global change in proteome profile of tamoxifen resistant MCF-7 breast cancer cells as a result of effect of EZH2 knockdown. Label Free Quantitative proteomics revealed a large number of proteins altered in acquired tamoxifen resistant cells compared to the sensitive cells. A total of 286 proteins were identified with normalized RT for each m/z out of which 86 proteins were upregulated by more than 1.3 fold and 98 proteins were down regulated by more than 1.3 fold in MCF-7 tamoxifen resistant breast cancer cells in comparison to the sensitive breast cancer cells. Upon EZH2 knockdown in tamoxifen resistant cells, a total of 115 proteins were found to be altered with 20 proteins upregulated by more than 1.3 fold and 49 proteins down regulated by more than 1.3 fold. Among the top upregulated proteins were L-lactate dehydrogenase A chain, Alpha and Gamma-enolase, Calreticulin, heat shock protein HSP-90-beta, Alpha-actinin-4, Elongation factor 1-alpha, Vimentin, Protein S100A6, Putative protein FAM10A5, Heterogeneous nuclear ribonucleoprotein A1 and Keratin 1. In addition, 15 proteins were found to be down regulated in EZH2si transfected tamoxifen sensitive cells which otherwise were highlyup regulated in resistant cells in the presence of normal level of EZH2. This indicates a possible regulation of these molecules by EZH2 leading to loss of resistance. Our data unveils important molecular players downstream to EZH2 knockdown leading to regain of sensitivity to tamoxifen in acquired tamoxifen resistance.Thus, EZH2 seems to exert its effects through regulation of metabolism, epithelial to mesenchymal transition and protein synthesis & folding. Hence, targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen intamoxifen-resistant cells.
2019-09-30 | PXD012609 | Pride
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2022-09-17 | GSE213492 | GEO
Project description:Gene expression profiling reveals a potential role of Butyroside D in melanogenesis inhibition in B16F10 cells. B16F10 cells were murine melanoma cell line, treated with 0.2 μM Butyroside D for 48 h. Microarray gene expression profiling was conducted for two biological replicates
2022-09-17 | GSE213491 | GEO