RNA-seq of cancer cell lines treated with T-025
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE101540 | GEO | 2018/05/01
REPOSITORIES: GEO
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Project description:CC-671 has been identified as an inhibitor of Cdc2-like kinase 2 (CLK2) and TTK in direct enzyme assays. CLK2 is a member of the CLK family that phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex as part of a regulatory mechanism for control of pre-mRNA splicing. SR proteins are a family of small nuclear ribonucleoprotein particle (snRNP) splicing factors involved in constitutive and alternative splicing. Monitoring specific phospho-biomarkers of CLK2 demonstrated that CC-671 inhibited phosphorylation of CLK2 substrates in cancer cells with mean IC50 of 549 nM in the triple negative breast cancer (TNBC) line CAL51. In this study, RNA sequencing approach was used to quantify the impact of CC-671 treatment on gene transcription and global alternative splicing in CAL51 cells. Differential exon usage analysis demonstrated that CC-671 changed alternative splicing of many genes. In addition, different sets of genes are impacted by CC-671 at both the alternative splicing and mRNA expression. Genes impacted by alternative splicing shared a set of common pathways with genes altered by mRNA expression. This result indicates that CC-671 regulates transcription via both gene expression and alternative splicing mechanisms.
2018-04-23 | GSE113426 | GEO
Project description:Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation. v6.5 mouse embryonic stem cells were untreated, treated with the Clk kinase inhibitor KH-CB19, or treated with DMSO as a negative control. Untreated cells were harvested and a single replicate was sequenced using a custom, ligation-based, stranded library preparation protocol. Treated cells were harvested at time 0 and at 2 hours post-treatment, and poly(A)-selected RNA-seq libraries were made from biological duplicates for each treatment/time, barcoded, and sequenced by strand-specific, paired-end sequencing using the Illumina TruSeq kit.
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Project description:Aberrant pre-mRNA splicing events in tumor cells generate tumor-specific splice junctions, translating potential neoantigens. RNA-seq was performed to examine whether a small molecule compound RECTAS affected splice patterns followed by neoantigen repertoire in mouse cancer cell lines.
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Project description:The Cdc2-like kinase (CLK)-family is a regulator of the splicing process. Here, we report the effect of Lorecivivint (SM04690), a CLK/DYRK inhibitor, on alternative splicing in the prostate cancer cell line 22Rv1. Lorecivivint treatment lead to impaired growth and disruption of several oncogenic pathways, including the androgen response, MYC, and Wnt/β-catenin hallmark pathways. Taken together, this data shows that alternative splicing is a pivotal process in prostate cancer and is suitable to be targeted.
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Project description:The Cdc2-like kinase (CLK)-family is a regulator of the splicing process. Here, we report the effect of Lorecivivint (SM04690), a CLK/DYRK inhibitor, on alternative splicing in the prostate cancer cell line 22Rv1. Lorecivivint treatment lead to impaired growth and disruption of several oncogenic pathways, including the androgen response, MYC, and Wnt/β-catenin hallmark pathways. Taken together, this data shows that alternative splicing is a pivotal process in prostate cancer and is suitable to be targeted.
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Project description:We aimed to study impact of CDC-like kinase (CLK) inhibitor CaNDY on OAS1 splicing manipulation. Our data indicates CaNDY treatment induces switching of OAS1 splice isoforms to provide an increased resistance to SARS-CoV-2 infection.
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Project description:SM08502 is a novel pan CDC-like kinase (CLK) inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. Previous evaluation of single agent CLK inhibition (SM04690) demonstrated inhibition of tumor progression and b-catenin/TCF transcriptional activity in CTNNB1-mutant endometrial cancer (EC). In-vitro analysis of SM08502 similarly decreases Wnt transcriptional activity and cellular proliferation while increasing cellular apoptosis. Examining transcriptomic analysis, SM08502 increases pathways involved in RNA metabolism and spliceosome. Examining alternative splicing (AS) events, SM08502 increased differential splicing compared to treatment with paclitaxel. AS regulation is an important post-transcriptional mechanism associated with the oncogenic process in many cancers, including EC.
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Project description:Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation.
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Project description:Description Alternative splicing plays critical roles in differentiation, development, and cancer. Using an integrated genomic approach, we have identified PRPF6, an RNA binding component of the pre-mRNA spliceosome, as an essential driver of oncogenesis in colon cancer. Importantly, PRPF6 is both amplified and overexpressed in colon cancer, and only colon cancer cells with high PRPF6 levels are sensitive to its loss. Our data clearly point to an important role for PRPF6 in colon cancer growth and suggest that a better understanding of its role in alternative splicing in colon cancer is warranted. To determine the specific alternative splice forms that PRPF6 regulates in colon cancer, we conducted the following experiment: Using two colon cancer cell lines (KM-12 and SW620) that have high PRPF6 levels, we inhibited PRPF6 expression using 2 independent siRNAs. We also tested the effect of U2 snRNP inhibition using both a siRNA targeting SF3B1 as well as spliceostatin A (a small molecule inhibitor of SF3B1). We then conducted RNA-seq to determine the gene expression and exonic changes that occur relative to either the non-targeting control siRNA (for siSF3B1 and siPRPF6) or the vehicle control (for spliceostatin A).
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