The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism

Biamonti, Giuseppe; Maita, Lucia; Montecucco, Alessandra

doi:10.3389/fonc.2018.00408

Cited by 18 publications

(12 citation statements)

References 203 publications

(258 reference statements)

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“…Thirdly, epigenetic regulations by histone modifications and DNA methylations could have led to some of the observed deregulations in alternative splicing 75 , 76 . And finally, more recently a connection between glucose metabolism and splicing efficacy was demonstrated 77 , which could also have contributed to aberrant splicing in our cancer samples. Further in-depth analyses are required to fully understand the genomic, epigenetic and metabolic causes behind the observed cMDT pattern.…”

Section: Discussionmentioning

confidence: 80%

Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Kahraman

Karakulak

Szklarczyk

et al. 2020

Sci Rep

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Under normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). To address the pathogenic impact of these switches, we have analyzed isoform-specific protein–protein interaction disruptions in 1,209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDT (cMDT) with the highest frequency in cancers of female reproductive organs. Interestingly, in contrast to the mutational load, cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers. cMDT tend to be located at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in protein translation and RNA splicing pathways. Interestingly, samples with mutations in the spliceosomal complex tend to have higher number of cMDT, while other transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.

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Section: Discussionmentioning

confidence: 80%

Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Kahraman

Karakulak

Szklarczyk

et al. 2020

Sci Rep

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show abstract

“…AS modulates the ratio between M1 and M2 isoforms of pyruvate kinase, in this way, determining the choice between aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). In turn, metabolites of the Krebs cycle impact splicing programs at different levels by modulating the activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs) [93]. In addition, increased levels of NADH induce the activation of the transcriptional corepressor CtBP involved in cell adhesion, metastatic invasion, drug-sensitivity, and RNA metabolism [94].…”

Section: As: An Important Player During Metabolic Stress and Neo-angimentioning

confidence: 99%

An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

Biamonti

Infantino

Gaglio

et al. 2019

Cells

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During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue-and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.

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“…Thirdly, epigenetic regulations by histone modifications and DNA methylations could have led to some of the observed deregulations in alternative splicing (Luco et al, 2011;Zhu et al, 2018). And finally, more recently a connection between glucose metabolism and splicing efficacy was demonstrated (Biamonti et al, 2018), which could also have contributed to aberrant splicing in our cancer samples. Further indepth analyses are required to fully understand the genomic, epigenetic and metabolic causes behind the observed cMDT pattern.…”

Section: Discussionmentioning

confidence: 80%

Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Kahraman

Mering

2019

Preprint

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Under normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). But what is the pathogenic impact of these switches and how are they driving oncogenesis? To address these questions, we have analyzed isoform-specific protein-protein interaction disruptions in 1209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDT (cMDT) between cancer types. While carcinomas of the head and neck, or brain, had none or only a few cMDT, cancers of the female reproduction organs showed the highest number of cMDT. Interestingly, in contrast to the mutational load, the number of cMDT was tissue-specific, i.e. cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers.cMDT showed a tendency to fall at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in enzyme signaling, protein translation, and RNA splicing pathways. Interestingly, no significant correlation between the number of cMDT and the number of coding or non-coding mutations could be identified. However, some transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.

show abstract

The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism

Cited by 18 publications

References 203 publications

Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an isoform-specific interaction network

An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network

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