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Exon Skipping of Ste20-Like Kinase Enhances Glycolysis and Tumor Progression by Activating Enolase 1 mediated Phosphoenolpyruvate Production

ABSTRACT: Dysregulated RNA splicing is activated in tumors; however, the metabolic landscape and consequent implications of this process remain largely unexplored. In this study, we identified exon skipping in Ste20-like kinase (SLK), resulting in a variant isoform of SLK (SLKv), which promotes glycolysis in tumor cells. Mechanistically, SLKv enhances the activity of enolase 1 (ENO1) by binding and phosphorylating the ENO1 serine 2 residue. This modification increases the efficiency of ENO1 in catalyzing the production of phosphoenolpyruvate (PEP). Notably, the accumulation of PEP further accelerates glycolysis by binding to and activating the glycolytic enzyme hexokinase 2 (HK2), phosphofructokinase muscle (PFKM), and phosphoglycerate mutase 1 (PGAM1). Meanwhile, transforming growth factor β (TGFβ) promotes exon skipping of SLK by upregulating the splicing factor KH RNA binding domain containing, signal transduction associated 1 (KHDRBS1). The application of antisense oligonucleotides (ASO) that target SLKv hinders glycolysis and tumorigenesis. These findings establish SLKv as a critical promoter of glycolysis and present a novel metabolic target for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299345 | GEO | 2025/06/17

REPOSITORIES: GEO

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Exon Skipping of Ste20-Like Kinase Enhances Glycolysis and Tumor Progression by Activating Enolase 1 mediated Phosphoenolpyruvate Production

Project description:Exon Skipping of Ste20-Like Kinase Enhances Glycolysis and Tumor Progression by Activating Enolase 1 mediated Phosphoenolpyruvate Production

| PRJNA1273951 | ENA

ENO1 couples HDAC1 to regulate histone lactylation and gene transcription

Project description:Histone deacetylases (HDACs) are essential transcriptional regulators that mediate gene expression through the complexes they are involved in. Thus, deciphering the HDAC-associated proteins is key to elucidating the underlying mechanisms. Here we present an efficient tool, termed heterobifunctional molecule-enabled proximity labeling strategy (BimPL), to investigate endogenous HDAC neighboring proteins in living cells. Leveraging BimPL and quantitative proteomics, we enable the robust capture of several known HDAC complexes as well as numerous putative HDAC interactors such as glycolytic enzyme enolase-1 (ENO1). Through biochemical studies and CUT&Tag analysis, we uncovered that nuclear ENO1 interacts with HDAC1, which in turn blunts the activity of HDAC1 via locally generated phosphoenolpyruvate (PEP), thereby mediating histone lysine lactylation (Kla) and gene transcription. Our study offers a versatile tool for systematic exploring endogenous protein complexes, as well as provides insight into the unidentified function of ENO1 in the regulation of histone Kla and liver tumor progression.

2025-05-01 | GSE291520 | GEO

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and glucose-independent tumor cell growth

Project description:Cancer cells must adapt metabolically to survive and proliferate when nutrients are limiting. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell growth. We found that glucose deprivation stimulated the re-wiring of the tricarboxylic acid (TCA) cycle and co-opting early steps of gluconeogenesis to promote cell proliferation under low glucose. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine, which was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. Mitochondrial PEP-carboxykinase (PCK2) was required for this glutamine-dependent metabolic reprogramming. PCK2 expression was dependent on the hypoxia-inducible factors (HIFs), and required to maintain tumor cell proliferation under limiting glucose availability. Elevated PCK2 expression is observed in several human tumor types, and enriched in tumor tissue from non-small cell lung cancer (NSCLC) patients. Our results define a novel role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

2015-10-15 | GSE66556 | GEO

Cellular senescence induced by down-regulation of PTBP1 correlates with exon skipping of mitochondrial related gene NDUFV3

Project description:As the most prevalent type of alternative splicing in animal cells, exon skipping plays an important role in expanding the diversity of transcriptome and proteome, thereby participating the regulation of diverse physiological and pathological processes such as development, aging and cancer. Cellular senescence serves as an anti-cancer mechanism could also contribute to individual aging. Although the dynamic changes of exon skipping during cellular senescence were revealed, its biological consequence and upstream regulator remain poorly understood. Here, by using human foreskin fibroblasts (HFF) replicative senescence as a model, we discovered that splicing factor PTBP1 was an important contributor for global exon skipping events during senescence. Down-regulated expression of PTBP1 induced senescence-associated phenotypes and related mitochondrial functional changes. Mechanistically, PTBP1 binds to the third exon of mitochondrial complex I subunit coding gene NDUFV3 and protects the exon from skipping. We further confirmed that exon skipping of NDUFV3 correlates with and partially contributes to cellular senescence and related mitochondrial functional changes upon PTBP1 knockdown. Together, we revealed for the first time that mitochondrial related gene NDUFV3 is a new downstream target for PTBP1-regulated exon skipping to mediate cellular senescence and mitochondrial functional changes.

2024-05-18 | GSE266081 | GEO

Inherited epigenetic repression of the Celf2a splicing factor mediates the amelioration of a Duchenne phenotype

Project description:Exon skipping is an effective strategy for the treatment of Duchenne Muscular Dystrophy (DMD). Natural exon skipping identified in several DMD cases can help with identifying novel therapeutic tools. Here, we demonstrate that CRISPR/Cas9 inactivation of the splicing factor Celf2a in a DMD-D44 background induces skipping of exon-45 and dystrophin rescue. Celf2a ablation could be compatible with life and curative since a DMD case with a milder symptomatology exists where exon-45 skipping occurs because of a Celf2a deficiency. We show that in this individual, Celf2a absence is due to inherited epigenetic silencing and that its repression is controlled by the lncRNA DUXAP8.

2020-07-01 | GSE139571 | GEO

SPLICER: A Highly Efficient Base Editing Toolbox That Enables in vivo Exon Skipping For Targeting Alzheimer’s Disease [RNA-seq]

Project description:Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which has broad applications in molecular and cellular biology, medicine and biotechnology. Existing exon skipping techniques include antisense oligonucleotides, targetable nucleases and base editors, which, while effective for specific applications at some target exons, remain hindered by shortcomings preventing their broader implementation including transient effects in the case of oligonucleotides or limiting PAM motifs, sequence context preferences for deaminases, and undesirable cryptic splicing in the case of gene editing tools. To overcome these limitations, we created SPLICER, a toolbox of next-generation base editors consisting of near-PAMless Cas9 nickase variants fused with different deaminases for simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences. Synchronized SA and SD editing not only improves exon skipping rates but also reduces aberrant outcomes such as cryptic splicing and intron retention. SPLICER enables editing of exon splice sites with high efficiency, including many exons refractory to splicing reprogramming by the native SpCas9 BEs. To demonstrate the therapeutic potential of SPLICER, we targeted APP exon 17, which contains the amino acid residues responsible for the formation of Aβ plaques in Alzheimer’s disease. SPLICER enabled precise and highly efficient exon skipping, which reduced the formation of Aβ42 peptides in vitro while inducing DNA editing and exon skipping in vivo within a humanized mouse model of Alzheimer’s disease. Overall, SPLICER is a widely applicable and highly efficient toolbox for exon skipping with broad therapeutic applications.

2023-12-10 | GSE246587 | GEO

SPLICER: A Highly Efficient Base Editing Toolbox That Enables in vivo Exon Skipping For Targeting Alzheimer’s Disease [miSeq]

2023-12-10 | GSE246586 | GEO

Targeted exon skipping with AAV-mediated split adenine base editors.

Project description:Techniques for exclusion of exons from mature transcripts have been applied as gene therapies for treating many different diseases. Since exon skipping has been traditionally accomplished using technologies that have a transient effect, it is particularly important to develop new techniques that enable permanent exon skipping. We have recently demonstrated that this can be accomplished using cytidine base editors for permanently disabling the splice acceptor of target exons. We now demonstrate the application of adenine-deaminase base editors to disrupt the conserved adenosine within splice acceptor sites for programmable exon skipping. We also demonstrate that by altering the amino acid sequence of the linker between the adenosine deaminase domain and the Cas9 nickase or by coupling the adenine base editor with a uracil glycosylase inhibitor, the DNA editing efficiency and exon skipping rates improve significantly. Finally, we developed a split base editor architecture compatible with adeno-associated viral packaging. Collectively, these results represent significant progress towards permanent in vivo exon skipping through base editing and, ultimately, a new modality of gene therapy for the treatment of genetic diseases.

2019-09-12 | GSE120125 | GEO

An Alternative Splicing Event Amplifies Evolutionary Differences Between Vertebrates

2015-09-01 | GSE69656 | GEO

An Alternative Splicing Event Amplifies Evolutionary Differences Between Vertebrates

Project description:Alternative splicing (AS) generates extensive transcriptomic and proteomic complexity. However, the functions of species- and lineage-specific splice variants are largely unknown. Here, we show that mammalian-specific skipping of exon 9 of PTBP1 alters its splicing regulatory activities and affects the inclusion levels of numerous exons. During neurogenesis, skipping of exon 9 reduces PTBP1 repressive activity so as to facilitate activation of a brain-specific AS program. Engineered skipping of the orthologous exon in chicken cells induces a large number of mammalian-like AS changes in PTBP1 target exons. These results thus reveal that a single exon skipping event in an RNA binding regulator directs numerous AS changes between species. The results further suggest that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems. This study contains two sets of samples: (Set 1) mRNA profiling of human 293 cells subjected to four different conditions in two biological replicates: non-targetting control siRNA, PTBP1 and PTBP2 siRNA, PTBP1 and PTBP2 siRNA with overexpression of full-length human PTBP1, PTBP1 and PTBP2 siRNA with overexpression of exon-excluded human PTBP1. (Set 2) mRNA profiling of chicken DT40 cells with 3 genotypes in two bioligcal replicates: wildtype cells, cells with PTBP1 exon 8 (orthologous to human PTBP1 exon 9) deleted in one allele, and cells with PTBP1 exon 8 deleted in both alleles.

2015-09-01 | E-GEOD-69656 | biostudies-arrayexpress

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