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Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248283 | GEO | 2024/03/11

REPOSITORIES: GEO

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Metabolic reprogramming of cancer cells by JMJD6-mediated alternative splicing

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

Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (ATAC-Seq)

Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.

2021-11-24 | GSE164504 | GEO

Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (RNA-Seq)

2021-11-24 | GSE164505 | GEO

Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high risk neuroblastoma

Project description:Neuroblastoma is the most common solid tumour in childhood. Prognosis remains poor for high risk cases despite the use of multimodal treatment, highlighting the urgent need for novel therapeutic strategies. Analysis of cell line drug sensitivity data suggested that among solid tumours neuroblastoma could be the most sensitive to treatment with indisulam (E7070). Indisulam is a clinical aryl sulphonamide and selective promoter of DCAF15-E3-ubiquitin ligase dependent degradation of the RNA splicing factor and transcriptional coactivator RBM39. Here, we demonstrate for the first time that indisulam is highly efficacious in vitro and in vivo in experimental models of neuroblastoma. Indisulam induced rapid depletion of RBM39, accumulation of splicing errors in mRNA and growth inhibition in a DCAF15-dependent manner. Global analysis of protein and RNA alterations in IMR32 cells demonstrated a significant overlap between mis-spliced RNA and decrease in protein levels. Pathway analysis indicated an enrichment for genes involved in cell cycle and one-carbon metabolism, including CDK4 and TYMS. Finally, indisulam induces mitochondrial dysfunction, metabolome perturbations, alterations to redox balance and NAD/NADH ratio in vitro. Metabolic changes were validated in IMR32 xenografts in vivo. Collectively, our data suggest that high-risk neuroblastomas, which are frequently MYCN/MYC-driven, may be particularly susceptible to the dual targeting of metabolism and RNA splicing with anticancer sulfonamides such as indisulam

2021-12-30 | GSE160446 | GEO

Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high-risk neuroblastoma

Project description:Neuroblastoma is the most common solid tumour in childhood and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be particularlysensitive to indisulam, a molecular glue that selectively targets the RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models indisulam induced rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlighted a particular disruption to cell cycle and metabolism. Metabolic profiling demonstrated metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour without relapse was observed in both xenografts and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss confirmed in vivo. Our data imply that dual targeting of metabolism and RNA splicing with anti-cancer sulfonamides such as indisulam is promising therapeutic approach for high-risk neuroblastoma.

2022-01-13 | PXD022164 | Pride

JMJD6 and NMYC binding examined by ChIP-seq in NMYC overexpressing CHP134 human neuroblastoma cells

Project description:JMJD6 (also known as PTDSR) is an important oncogene that is upregulated in 17q21-ter gained neuroblastoma.It plays a role in E2F and N-Myc-regulated gene pathways and neuroblastoma tumorigenesis Using ChIP-Seq, we profiled JMJD6 and NMYC binding in the NMYC overexpressing neuroblastoma cell line. We identified the genomic location of JMJD6 and NMYC binding peaks across the human genome.

2019-06-23 | GSE129588 | GEO

Pol2 binding examined by ChIP-seq in inducible JMJD6 knockdown neuroblastoma cells

Project description:JMJD6 is an important oncogene that is upregulated in 17q21-ter gained neuroblastoma.It plays a role in E2F and N-Myc-regulated gene pathways and neuroblastoma tumorigenesis Using ChIP-Seq, We profiled RNA polymerase 2 binding in doxycycline inducible JMJD6 shRNA CHP-134 neuroblastoma cells, treated with either doxycycline or vehicle control. We identified a list of genes with reduced RNA Pol II binding peaks at their gene promoters as a result of the JMJD6 knockdown. GSEA analysis showed that the top four gene sets, with most considerable reduction in RNA Pol II binding peaks at gene promoters, were E2F target genes, G2M checkpoint genes, mitotic spindle genes, and Myc target genes.

2019-06-23 | GSE112919 | GEO

Oncogenic MYC induces a dependency on the spliceosome in human cancer

Project description:c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers. Examination of intron rentention in MYC-ER HMECs, in 4 conditions

2015-09-03 | E-GEOD-66182 | biostudies-arrayexpress

CGH analysis of mouse mammary gland tumors from eight genetically-engineered mouse models

Project description:Background. Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene induced tumorigenesis to overcome these biologic obstacles. We employed array CGH for 8 genetically-engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis. Results. Unlike many other mammary tumor models, the MMTV-Myc tumors displayed few CNVs except for amplification of distal mouse chromosome 11 in 80% of the tumors (syntenic to human 17q23-qter often amplified in human breast cancer). Analyses of candidate genes located in this region identified JMJD6 as an epigenetic regulatory gene that cooperates with Myc to enhance tumorigenesis. It suppresses Myc-induced apoptosis under varying stress conditions through inhibition of p19ARF mRNA and protein, leading to reduced levels of p53. JMJD6 binds to the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a. JMJD6 overexpression in MMTV-Myc cell lines increases tumor burden, induces EMT and greatly enhances tumor metastasis. Importantly, we demonstrate that co-expression of high levels of JMJD6 and MYC is associated with poor prognosis for human ER+ breast cancer patients. Conclusions. A novel epigenetic mechanism has been identified for how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. Given the pleotropic pro-tumorigenic activities of JMJD6, it may be useful as a prognostic factor and a therapeutic target for Myc-driven mammary tumorigenesis.

2016-11-18 | GSE75331 | GEO

Global transcriptional profiling of wild type and LATS1/2 KO CAL27 cells in response to indisulam

Project description:mRNA sequencing of WT and LATS1/2 KO CAL27 cells were treated with indisulam 1 μM for 24hr to profile and characterize dysregulated pathways and alternative splicing in response to indisulam

2024-07-21 | GSE268568 | GEO

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