Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor
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ABSTRACT:
PROVIDER: PRJNA1043161 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26894078_1.fastq.gz | Fastqsanger.gz | |||
| SRR26894078_2.fastq.gz | Fastqsanger.gz | |||
| SRR26894079_1.fastq.gz | Fastqsanger.gz | |||
| SRR26894079_2.fastq.gz | Fastqsanger.gz | |||
| SRR26894080_1.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, or JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a “molecular glue” that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is coupled with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.
2024-03-11 | GSE248283 | GEO
Project description:Chromosome 17q gain occurs frequently in MYC-driven tumors including high-risk neuroblastoma. However, the biological consequences of this genetic event remain elusive. Here we show that JMJD6, frequently amplified at the chromosome 17q25 locus, is one of the essential genes to neuroblastoma cells that are engaged in pathways of mitochondrial metabolism, RNA processing and protein homeostasis. JMJD6 cooperates with MYC in cellular transformation and promotes cancer cell proliferation and tumor growth. Mechanistically, JMJD6 physically interacts with RNA-processing machinery to regulate the alternative splicing and protein synthesis. Notably, JMJD6 controls the alternative splicing of glutaminase (GLS), kidney-type glutaminase (KGA) and glutaminase C (GAC), a rate-limiting enzyme of glutaminolysis, and, consequently, the central carbon metabolism in neuroblastoma. Our findings indicate that JMJD6 coordinates with MYC in tumorigenesis by regulating cancer-promoting metabolic programs through an alternative pre-mRNA splicing mechanism.
2023-10-31 | GSE185867 | GEO
Project description:The 2-oxoglutarate dependent protein JMJD6 acts as a lysyl hydroxylase on specific residues of the splicing factor U2AF2. To understand the molecular roles of JMJD6 in normal haematopoiesis and identify any role of JMJD6 in splicing, we performed RNA-sequencing on Lin-Sca1+Kit+ (LSK) haematopoietic stem and progenitor cells (HSPCs) derived from young mice.
2021-03-05 | GSE168283 | GEO
Project description:Post-transcriptional modifications of tumor suppressors, including microRNA-mediated downregulation, are important events in tumor progression. To identify microRNAs involved in oncogenic transformation, we examined global microRNA profiles of three ras transgenic zebrafish models. Four microRNAs are upregulated in all transgenic systems. Analysis of the predicted targets shows that three of them target Jmjd6, and overexpression of Jmjd6 in ras transformed melanocytes blocks proliferation and melanoma development. We found that Jmjd6 functions to regulate splicing of the tumor suppressor cdkn1a/p21. Truncated cdkn1a/p21 transcripts, lacking the PCNA binding domain, accumulate in ras-expressing melanocytes during melanoma development. These findings implicate Jmjd6 in a novel mechanism for inactivation of a major tumor suppressor pathway in melanoma.
2017-01-01 | GSE37015 | GEO
Project description:Metabolic reprogramming of cancer cells by JMJD6-mediated alternative splicing
| PRJNA771064 | ENA
Project description:The Jumonji domaining-containing protein JMJD6 is a 2-oxoglutarate dependent dioxygenase that has been implicated in a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing and co-transcriptional processing. Although not all studies agree, JMJD6 has been reported to catalyse both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and the indirect implication of JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a site of reported prolyl hydroxylation within a lysine-rich region of the bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalysed by Jmjd6. This prompted a wider search for JMJD6-catalysed protein modifications deploying mass spectrometric methods designed to identify novel substrate associations and facilitate analysis of lysine-rich regions by LC-MSMS. Using derivatization of lysine with propionic anhydride to improve the analysis of tryptic peptides and a pharmacological inhibitor of JMJD6 to stabilise enzyme/substrate associations, we report over 100 sites of JMJD6-catalysed lysyl hydroxylation on 48 protein substrates including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in this study have been associated with membraneless organelle formation. Taken together with findings implicating lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia. Note, this dataset corresponds to Figure 3 of the published manuscript; which employs a substrate-trapping methodology to identify novel substrates of JMJD6 by label free DIA approach.
2022-08-02 | PXD031155 | Pride
Project description:Jumonji C-domain containing protein 6 (JMJD6), an iron (Fe2+) and a-ketoglutarate (a-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line-and patient-derived xenograft models with safety. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in clinic.
2022-08-31 | GSE201988 | GEO
Project description:The Jumonji domaining-containing protein JMJD6 is a 2-oxoglutarate dependent dioxygenase that has been implicated in a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing and co-transcriptional processing. Although not all studies agree, JMJD6 has been reported to catalyse both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and the indirect implication of JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a site of reported prolyl hydroxylation within a lysine-rich region of the bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalysed by Jmjd6. This prompted a wider search for JMJD6-catalysed protein modifications deploying mass spectrometric methods designed to identify novel substrate associations and facilitate analysis of lysine-rich regions by LC-MSMS. Using derivatization of lysine with propionic anhydride to improve the analysis of tryptic peptides and a pharmacological inhibitor of JMJD6 to stabilise enzyme/substrate associations, we report over 100 sites of JMJD6-catalysed lysyl hydroxylation on 48 protein substrates including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in this study have been associated with membraneless organelle formation. Taken together with findings implicating lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia. This deposition contains all hydroxylysine assignment data.
2022-08-02 | PXD031221 | Pride
Project description:Clear cell renal cell carcinoma (ccRCC) represents a lethal disease and classically resistant to cytotoxic chemotherapy, highlighting the importance of identifying new therapeutic vulnerabilities. We performed a functional siRNA screening for all 2-oxoglutarate (2-OG)-dependent enzymes in ccRCC using 3-D soft agar colony formation assay, and combined with TCGA data, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumorigenesis. Downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq and RNA-seq identified that JMJD6 can transcriptionally regulate the expression of diacylglycerol O-acyltransferase 1 (DGAT1) by co-occupying the target gene promoter with H3K4me3. Downregulation of JMJD6 caused decreased expression of DGAT1 at both mRNA and protein level. Inhibition or depletion of DGAT1 induced decreased cell growth in vitro or inhibited tumor growth in vivo. Mechanistically, decreased DGAT1 caused decreased LD formation in ccRCC, while restoration of JMJD6 expression can restore DGAT1 level, and LD formation as well as cell growth. In summary, JMJD6 is essential for ccRCC lipid storage and tumorigenesis through a DGAT1-dependent signaling. Therefore, the JMJD6-DGAT1 axis serves as a potential therapeutic avenue for ccRCC.
2022-06-27 | GSE182888 | GEO
Project description:pre-mRNA splicing in C. elegans
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