Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukemia cells
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ABSTRACT:
PROVIDER: PRJNA514230 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8428602_1.fastq.gz | Fastqsanger.gz | |||
| SRR8428602_2.fastq.gz | Fastqsanger.gz | |||
| SRR8428603_1.fastq.gz | Fastqsanger.gz | |||
| SRR8428603_2.fastq.gz | Fastqsanger.gz | |||
| SRR8428604_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic modifiers were important players in the development of hematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyzes the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukemia progression and resistance to therapy targeting on BCR-ABL remain unclear. Here we found SETD2 acted as a tumor suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell’s imatinib sensitivity and enhanced the chemotherapeutic effect.
2019-07-19 | GSE124894 | GEO
Project description:ObjectivesEpigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.Materials and methodsThe level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34+ CD38- leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small-molecule inhibitor JIB-04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP-quantitative PCR were performed to verify putative downstream targets.ResultsSETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.ConclusionsOur study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.
| S-EPMC6668982 | biostudies-literature
Project description:Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Imatinib mesylate has emerged as the leading compound to treat chronic myeloid leukemia (CML), through its inhibition of Bcr- Abl tyrosine kinases, and other cancers. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new BCR-ABL inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib showed large interest since the introduction of the nilotibin. To identify the cellular pathways affected by new synthesized compounds, we applied mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in K562 cells that were untreated or treated with imatinib and imatinib derivates. Further, the global proteome of the K562 cells treated with imatinib were quantitatively compared with the cells treated with the new compounds. This study enriched our knowledge about direct cellular targets of kinase selective drugs. Further the results offered important new knowledge for gaining insights into the structural effects of action of the new compounds. Samples were analyzed on a longer column (30cm) and a longer gradient (180min). Raw data files were processed with Mascot distiller 2.3. The mgf files were searched with Mascot daemon 2.3. The quantification was also done by Mascot Distiller. All data was stored in ms_lims. The manual validation of false peptide ratios was done with Rover (part of ms_lims). Fixed modifications: none. Variable modifications: acetylation of peptide N-terminus, pyroglutamate formation of N-terminal glutamine, methionine oxidation. Enzyme: trypsine with one missed cleavage allowed. Precursor mass tolerance: 10 ppm. Peptide fragment mass tolerance: 0.5 Da Quantitation method: SILAC arginine and lysine +6 Da. Overview of the 17 different analyses: B SK23 vs DMSO C Y22 vs DMSO D SK20 vs DMSO E Y18 vs DMSO I SK20 vs DMSO K Y18 vs DMSO O Y22 vs DMSO R Imatinib vs Water Z Imatinib vs Water J SK20 vs Imatinib M SK23 vs Imatinib N Y22 vs Imatinib P SK23 vs Imatinib Q Y18 vs Imatinib S Y22 vs Imatinib T SK20 vs Imatinib Y Y18 vs Imatinib
2014-06-30 | PXD000216 | Pride
Project description:The histone methyltransferase SETD2 is responsible for the transcription-coupled trimethylation of histone H3 lysine 36 (H3K36me3) on all protein-coding genes through its direct interaction with the elongating form of RNA polymerase II. In mice, Setd2 is required for embryonic development, as the Setd2-null mice are embryonic lethal due to impaired vascular remodeling. In human, SETD2 is frequently mutated in various types of cancer, thus representing one of the major chromatin-modification defects that drive tumorigenesis. Notably, recent studies suggest that, despite the central roles of their catalytic activities, many chromatin modifiers contain important non-catalytic (so-called “moonlighting”) functions, which are largely substantiated by their roles in protein-protein interactions. This notion is somewhat consistent with the observation that the cancer-associated SETD2 mutations are seemingly localized throughout the whole protein, thus raising a question whether the major function(s) of SETD2 is solely dependent on its methyltransferase activity. As an answer to this question, in this short report, we have established a site-specific Setd2 knock-in mouse model harboring a patient-derived, catalytic dead Setd2 and have provided clear evidence supporting that the requirement of Setd2 in mouse embryonic development is definitely dependent on its methyltransferase activity. However, it is also notable that, in comparison with the Setd2-null mice, the Setd2 catalytic dead mice showed slightly mild defects in embryonic development and gene expression changes, suggesting potential non-catalytic functions of Setd2, which could be studied in the future by using these different Setd2 mouse models.
2024-01-01 | GSE241154 | GEO
Project description:The domains of SETD2, a known histone methyltransferase were investigated for specific interaction partners and function using a number of biochemical assays and affinity purification mass spectrometry. The C-terminal domain, named SETD2C, was identified to interact with hnRNP-L through a previously uncharacterized domain. These findings demonstrate the crosstalk between the transcription and splicing machinery.
2021-02-01 | PXD019538 | Pride
Project description:The domains of SETD2, a known histone methyltransferase were investigated for specific interaction partners and function using a number of biochemical assays and affinity purification mass spectrometry. The C-terminal domain, named SETD2C, was identified to interact with hnRNP-L through a previously uncharacterized domain. These findings demonstrate the crosstalk between the transcription and splicing machinery.
2021-02-01 | PXD019376 | Pride
Project description:The domains of SETD2, a known histone methyltransferase were investigated for specific interaction partners and function using a number of biochemical assays and affinity purification mass spectrometry. The C-terminal domain, named SETD2C, was identified to interact with hnRNP-L through a previously uncharacterized domain. These findings demonstrate the crosstalk between the transcription and splicing machinery.
2021-02-01 | PXD022946 | Pride
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136743 | GEO
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136742 | GEO
Project description:Several lines of recent evidence support a role for chromatin in splicing regulation. Here we show that splicing can also contribute to histone modification, which implies a bidirectional communication between epigenetics and RNA processing. Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with H3K36me3 relative to intronless genes. In intron-containing genes, H3K36me3 marking is proportional to transcriptional activity, whereas in intronless genes H3K36me3 is always detected at much lower levels. Furthermore, splicing inhibition impairs recruitment of H3K36 methyltransferase HYPB/Setd2 and reduces H3K36me3, whereas splicing activation has the opposite effect. Moreover, the increase of H3K36me3 correlates with the length of the first intron, consistent with the view that splicing enhances H3 methylation. We propose that splicing is mechanistically coupled to recruitment of HYPB/Setd2 to elongating RNA Polymerase II. This experiment proposes to profile genome-wide binding profiles by ChIP-seq (Illumina, 36 bp tags) of RNA polymerase II (one biological replicate), the histone modification H3K36me3 (2 replicates) and a reference control input sample (genomic DNA after reverse cross-link, one replicate) in a human H1299 lung carcinoma cell line *** Raw data not provided for Samples GSM766322-GSM766324.
2011-07-25 | E-GEOD-30902 | biostudies-arrayexpress