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PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

ABSTRACT: PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

PROVIDER: PRJNA991917 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25176971_1.fastq.gz	Fastqsanger.gz
	SRR25176971_2.fastq.gz	Fastqsanger.gz
	SRR25176972_1.fastq.gz	Fastqsanger.gz
	SRR25176972_2.fastq.gz	Fastqsanger.gz
	SRR25176973_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

Project description:Protein phosphatase 2A (PP2A) is a promiscuous enzyme affecting cellular physiology. It is unclear however, which of the cellular processes are most perturbed upon PP2A inhibition and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to PP2A inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Changed phosphorylation endows LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events in PP2A-inhibited cells affect predominantly regulators of genomic integrity. Finally, LB-100-evoked alternative splicing is predicted to be a source of neoantigens that can improve cancer treatment responses to immune modulators. Our findings provide a potential explanation for the pre-clinical and clinical observations that PP2A inhibition sensitizes cancer cells to immune checkpoint blockade and genotoxic agents.

2024-04-11 | GSE236625 | GEO

PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

Project description:Protein phosphatase 2A (PP2A) is a promiscuous enzyme that acts on many aspects of cellular physiology. It remains unclear however, which of the cellular processes are most perturbed upon inhibition of PP2A and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to phosphatase 2A (PP2A) inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. These phosphorylation changes endow LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events were enriched in PP2A-inhibited cells affecting the splicing of regulators of genomic integrity and DNA damage response. Finally, alternatively spliced transcripts downstream to LB-100 are predicted to be a source of neoantigens that can improve cancer treatment outcomes in response to immune checkpoint modulators. Collectively, our findings provide a potential explanation for the pre-clinical and clinical observations that inhibition of PP2A results in increased sensitivity of cancer cells to immune checkpoint blockade and DNA damaging agents.

2024-06-16 | PXD043658 | Pride

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-21 | PXD012172 | Pride

The spliceosome is an exploitable vulnerability in RB1-mutant cancer

Project description:The spliceosome is an exploitable vulnerability in RB1-mutant cancer

| PRJNA606793 | ENA

HALTING THE NAD+-DEPENDENT DEACETYLASE SIRT6 UNVEILS SPLICEOSOME DEREGULATION AS EXPLOITABLE VULNERABILITY FOR AGGRESSIVE MYELOMA

Project description:Epigenetic defects play a major role in tumors, by promoting aggressiveness, drug resistance and disease progression. Targeting enzymes responsible for these changes holds promise but the knowledge-gap and lack of selective inhibitors severely hampers their clinical use. Recently, we found that Multiple Myeloma (MM) cells exhibit high level of NAD+-dependent deacetylase SIRT6 as an adaptive response to their intrinsic genomic instability. Here we focus on splicing-related events resulting as the most enriched pathways among MM patients with high SIRT6 levels. CoMMpass dataset analysis confirmed the prognostic role of SIRT6 in MM, with its presence correlating with poor outcome and aggressiveness. Transcriptome analysis of SIRT6-depleted MM cells indicated spliceosome perturbation as critical: chemical and genetic approaches resulted in enhanced anti-MM activity of spliceosome modulator Sudamycin D6 (SD6) thus supporting RNA splicing deregulation as vulnerability for these cells. Spliceosome is a therapeutic weakness for MYC-driven cancer, as such we found that while c-MYC oncogene loss shows resistance, its re-expression enhances efficacy of tested strategy. A direct role for SIRT6 on splicing factors genes was also demonstrated using ChIP-seq analyses. Overall, the dysregulated spliceosome activity triggered by epigenetic machinery blocking represents a novel therapeutic strategy for poor-prognosis subset of MM patients overexpressing c-MYC

2022-08-19 | GSE211342 | GEO

Cdc14 and PP2A Phosphatases Cooperate to Shape Phosphoproteome Dynamics during Mitotic Exit

Project description:Temporal control over protein phosphorylation and dephosphorylation is crucial for accurate chromosome segregation and for completion of the cell division cycle during exit from mitosis. In budding yeast, the Cdc14 phosphatase is thought to be a major regulator at this time, while in higher eukaryotes PP2A phosphatases take a dominant role. Here, we use time-resolved phosphoproteome analysis in budding yeast to evaluate the respective contributions of Cdc14 and the two main PP2A isoforms, PP2A(Cdc55) and PP2A(Rts1). This reveals an overlapping requirement for all three phosphatases during mitotic progression. Cdc14 instructs the sequential pattern of phosphorylation changes, in part through its preferential recognition of serine-based cyclin-dependent kinase (Cdk) substrates. PP2A(Cdc55) and PP2A(Rts1) in turn exhibit a broad substrate spectrum with some selectivity for phospho-threonines and a role for PP2A(Rts1) in sustaining Aurora kinase activity. Our results illustrate synergy and coordination between phosphatases as they orchestrate phosphoproteome dynamics during mitotic progression.

2019-11-12 | PXD012860 | Pride

Dopamine Receptor Antagonists and Radiation Create a Metabolic Vulnerability in Mouse Models of Glioblastoma

Project description:Dopamine Receptor Antagonists and Radiation Create a Metabolic Vulnerability in Mouse Models of Glioblastoma

| PRJNA695232 | ENA

Spliceosome iCLIP

Project description:Spliceosome iCLIP

| PRJEB27592 | ENA

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-18 | GSE124510 | GEO

Hotspot mutations induce metabolic reprogramming and vulnerability to serine deprivation

Project description:Cancer-associated mutations in the spliceosome gene create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we provide evidence that aberrant splicing by mutant alters the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also find that mutant induces vulnerability to deprivation of the nonessential amino acid serine, which is mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability is manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice is able to inhibit the growth ofMUT xenografts. These findings describe a novel role for mutations in altered energy metabolism, and they offer a new therapeutic strategy againstMUT cancers.

2019-12-31 | GSE134475 | GEO

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