Minor intron splicing efficiency increases with the development of lethal prostate cancer

Augspach, Anke; Drake, Kyle D.; Roma, Luca; Qian, Ellen; Lee, Se Ri; Clarke, Declan; Kumar, Sushant; Jaquet, Muriel; Gallon, John; Bolis, Marco; Triscott, Joanna; Galván, José A.; Chen, Yu; Thalmann, George N.; Julio, Marianna Kruithof-de; Theurillat, Jean-Philippe; Wuchty, Stefan; Gerstein, Mark; Piscuoglio, Salvatore; Kanadia, Rahul N.; Rubin, Mark A.

doi:10.1101/2021.12.09.471104

Cited by 5 publications

(4 citation statements)

References 78 publications

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“…Cells with higher levels of these snRNAs had higher proliferation rate and spent a shorter time in the G1 phase. This observation aligns with data showing that the knockdown of U6atac snRNA, as well as several other components of the minor spliceosome, resulted in the downregulation of genes related to the cell cycle and DNA repair and blocked the proliferation of cancer cells but not non-cancer cell lines 110 .…”

Section: Discussionsupporting

confidence: 90%

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells

Shender,

Anufrieva,

Shnaider

et al. 2024

Nat Commun

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Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.

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Section: Discussionsupporting

confidence: 90%

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells

Shender,

Anufrieva,

Shnaider

et al. 2024

Nat Commun

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“…This variation in the responsive nature of minor introns complicates the construction of a comprehensive list of introns that are dependent on the minor spliceosome. Nevertheless, development of such a list is essential for benchmarking bioinformatics pipelines aimed at annotating introns and for identifying the biological pathways regulated by the minor spliceosome, as the minor spliceosome has recently been suggested as a potential therapeutic target for cancer (27, 28). We therefore decided to analyze all currently available transcriptomic datasets in which the minor spliceosome was inhibited (Table S2) , yielding a comprehensive list of experimentally validated, “responsive” introns in the five model organisms: human ( Homo sapiens ), mouse ( Mus musculus ), zebrafish ( Danio rerio ), fruit fly ( Drosophila melanogaster ) and maize ( Zea mays) .…”

Section: Resultsmentioning

confidence: 99%

Taxonomy of introns, their evolution, and the role of minor introns in stress response

Olthof

Schwoerer

Weber

et al. 2022

Preprint

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Despite the high conservation of minor introns across eukaryotic supergroups, specific lineages have completely lost minor intron splicing, which has raised questions about their evolution and purpose. Addressing these questions requires identification of the introns that are affected by minor spliceosome inhibition. To this end, we applied principles of Linnaean taxonomy combined with position-weight matrices to produce five intron classes: minor, minor-like, hybrid, major-like and major. We classified introns across the genomes of 263 species of six eukaryotic supergroups, which can be viewed at the Minor Intron Database (MIDB). Transcriptomic analysis revealed that ~40% of the minor introns are responsive to minor spliceosome inhibition, while an additional 5% of the minor-like and hybrid introns are also affected. We propose that minor-like introns represent an intermediate in the conversion of minor to major introns and uncover the importance of a guanine at the -1 position of the 5′ splice site in facilitating this shift in spliceosome dependence. Finally, we find that minor introns are aberrantly spliced in fish and plants upon cold stress, thereby providing a potential explanation for their high degree of conservation in these lineages.

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“…Reversal of ADT resistance was significantly enhance by inhibition of U6atac expression. 61 These data imply the importance of spliceosome mediated mechanisms and their potential as novel therapeutic targets to inhibit and/or reverse LP-PCa (Fig. 1).…”

Section: Role Of Lsd1 In Lp-pcamentioning

confidence: 87%

Phenotypic Plasticity - Alternate Transcriptional Programs Driving Treatment Resistant Prostate Cancer

et al. 2022

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Androgen deprivation therapy (ADT) that antagonizes androgen receptor (AR) signaling has made significant increases to overall survival of prostate cancer patients. However, ADT is not curative, and patients eventually progress to castration resistant disease (CRPC). It has become evident that a subset of prostate cancers acquire ADT resistance through mechanisms independent of AR alteration or reprogramming of AR signaling. This approximately involves a quarter of prostate cancers progressing on ADT. Collectively, these tumors evolve via phenotypic plasticity and display the activation of developmental and stemness gene signatures as well as transitional programs including an epithelial-mesenchymal phenotype. Currently, no successful treatments exist for prostate cancer patients to inhibit or reverse prostate tumor progression that utilizes mechanisms of epi-plasticity. This overview will discuss epigenetic mechanisms that mediate phenotypic plasticity and the potential for targeting the epigenome to create a novel direction for combination strategies involving epigenetic therapy to provide durable response.

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Minor intron splicing efficiency increases with the development of lethal prostate cancer

Cited by 5 publications

References 78 publications

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells

Taxonomy of introns, their evolution, and the role of minor introns in stress response

Phenotypic Plasticity - Alternate Transcriptional Programs Driving Treatment Resistant Prostate Cancer

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