Nuclear IQGAP1 promotes gastric cancer cell growth by altering the splicing of a cell-cycle regulon in co-operation with hnRNPM
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ABSTRACT:
PROVIDER: PRJNA609974 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11218912_1.fastq.gz | Fastqsanger.gz | |||
| SRR11218912_2.fastq.gz | Fastqsanger.gz | |||
| SRR11218913_1.fastq.gz | Fastqsanger.gz | |||
| SRR11218913_2.fastq.gz | Fastqsanger.gz | |||
| SRR11218914_1.fastq.gz | Fastqsanger.gz |
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Project description:Heterogeneous nuclear ribonucleoproteins (hnRNPs) play a decisive role in alternative splicing, regulating the cell proteome and contributing to human diseases. hnRNPs are nuclear proteins but it is still an open question where they localize in the nucleus and what determines their tethering to nuclear assemblies in response to signals. Here we report that IQGAP1, a cytosolic scaffold protein, localizes in the nucleus of gastric cancer cells acting as a tethering module for hnRNPM as well as other spliceosome components. The IQGAP1-hnRNPM interaction alters, among others, the alternative splicing of ANAPC10 and is required for the response of hnRNPM to heat-induced stress signals. Together, IQGAP1 and hnRNPM promote gastric cancer cell growth while their depletion leads to cell cycle arrest and halts tumour progression. We propose that IQGAP1 localizes in the nucleus and coordinates gastric tumour growth by recruiting, in response to stress-signals, spliceosome components that drive cell cycle progression.
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Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program. RNAseq for control, hnRNPM siRNA treated lung metastatic LM2 clonal line, derived from the mesenchymal MDA-MB-231 cells
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Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.
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Project description:We performed hnRNPM iCLIP to identify the potential targets.
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Project description:The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome-scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they co-regulate a set of cassette exon events, with the majority showing discordant splicing regulation. hnRNPM discordantly regulated splicing events show a positive correlation with splicing during EMT while concordant splicing events do not, highlighting the antagonistic role of hnRNPM and ESRP1 during EMT. Motif enrichment analysis near co-regulated exons identifies guanine-uridine rich motifs downstream of hnRNPM-repressed and ESRP1-enhanced exons, supporting a model of competitive binding to these cis-elements to antagonize alternative splicing. The set of co-regulated exons are enriched in genes associated with cell-migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of co-regulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtypes. In conclusion, hnRNPM and ESRP1 co-regulate antagonistically a set of alternative splicing events that occur during EMT. This regulation is likely mediated through competition for the same intronic binding sites downstream of variable exons. hnRNPM and ESRP1 regulated splicing events are associated with breast cancer survival.
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