Similar Datasets
Project description:Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated spliceosomal components in cancer. Recent studies additionally imply an involvement of the wildtype protein in tumor progression, but the underlaying mechanism remains elusive. Here we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF) 1α. SF3B1 directly interacts with HIF1a, augments HIF1a-HIF1b heterodimer binding to hypoxia response elements in vivo and enhances transactivation of HIF target genes. In human patients, primary patient cells and in a mouse model of pancreatic ductal adenocarcinoma (PDAC), efficient HIF1a-signalling relies on SF3B1. Monoallelic deletion of Sf3b1 in this mouse tumor model severely delays tumor initiation and development and diminishes HIF target gene transcription, glucose uptake and proliferation in corresponding tumor organoids in hypoxia, while splicing remains functional. Here, we define a subset of aggressive chromophobe renal cell carcinomas (chRCCs) able to transcriptionally compensate monoallelic SF3B1 loss, a feature that correlates with poor prognosis and lymph node spread and we show that the oncogenic hotspot mutation SF3B1K700E has reduced co-activation efficiency. Also, we report increased sensitivity of cells with low levels of SF3B1 to the HIF-inhibitor PX-478. These findings reveal a splicing-independent, tumor promoting function of SF3B1, important in the pathogenesis of PDAC and other cancers.
2022-06-22 | GSE201461 | GEO
Project description:Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated spliceosomal components in cancer. Recent studies additionally imply an involvement of the wildtype protein in tumor progression, but the underlaying mechanism remains elusive. Here we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF) 1α. SF3B1 directly interacts with HIF1a, augments HIF1a-HIF1b heterodimer binding to hypoxia response elements in vivo and enhances transactivation of HIF target genes. In human patients, primary patient cells and in a mouse model of pancreatic ductal adenocarcinoma (PDAC), efficient HIF1a-signalling relies on SF3B1. Monoallelic deletion of Sf3b1 in this mouse tumor model severely delays tumor initiation and development and diminishes HIF target gene transcription, glucose uptake and proliferation in corresponding tumor organoids in hypoxia, while splicing remains functional. Here, we define a subset of aggressive chromophobe renal cell carcinomas (chRCCs) able to transcriptionally compensate monoallelic SF3B1 loss, a feature that correlates with poor prognosis and lymph node spread and we show that the oncogenic hotspot mutation SF3B1K700E has reduced co-activation efficiency. Also, we report increased sensitivity of cells with low levels of SF3B1 to the HIF-inhibitor PX-478. These findings reveal a splicing-independent, tumor promoting function of SF3B1, important in the pathogenesis of PDAC and other cancers.
2022-06-22 | GSE201427 | GEO
Project description:Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated spliceosomal components in cancer. Recent studies additionally imply an involvement of the wildtype protein in tumor progression, but the underlaying mechanism remains elusive. Here we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF) 1α. SF3B1 directly interacts with HIF1a, augments HIF1a-HIF1b heterodimer binding to hypoxia response elements in vivo and enhances transactivation of HIF target genes. In human patients, primary patient cells and in a mouse model of pancreatic ductal adenocarcinoma (PDAC), efficient HIF1a-signalling relies on SF3B1. Monoallelic deletion of Sf3b1 in this mouse tumor model severely delays tumor initiation and development and diminishes HIF target gene transcription, glucose uptake and proliferation in corresponding tumor organoids in hypoxia, while splicing remains functional. Here, we define a subset of aggressive chromophobe renal cell carcinomas (chRCCs) able to transcriptionally compensate monoallelic SF3B1 loss, a feature that correlates with poor prognosis and lymph node spread and we show that the oncogenic hotspot mutation SF3B1K700E has reduced co-activation efficiency. Also, we report increased sensitivity of cells with low levels of SF3B1 to the HIF-inhibitor PX-478. These findings reveal a splicing-independent, tumor promoting function of SF3B1, important in the pathogenesis of PDAC and other cancers.
2022-06-25 | GSE206703 | GEO
Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α
| PRJNA831827 | ENA
Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α [ChIP-Seq]
| PRJNA831832 | ENA
Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α [RNA-Seq]
| PRJNA831709 | ENA
Project description:SF3B1 promotes glycolysis and tumor malignancy through splicing-independent activation of HIF1α [RNA-Seq murine organoids]
| PRJNA851799 | ENA
Project description:BackgroundRecently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored.MethodsUsing the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA.ResultsTranscriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway.ConclusionsOur findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
| S-EPMC8762886 | biostudies-literature
Project description:Aberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5' and 3' splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.
| S-EPMC7969951 | biostudies-literature
Project description:Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.
| S-EPMC5309811 | biostudies-other