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SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

ABSTRACT: Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116631 | GEO | 2019/12/31

REPOSITORIES: GEO

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SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

Project description:Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.

2020-04-27 | GSE149370 | GEO

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells

| PRJNA628515 | ENA

SFPQ interacted proteins in HEK293T nucleus and cytoplasm

Project description:Splicing factor proline and glutamine rich (SFPQ), DNA- and RNA binding protein, is crucial in various nuclear processes, including paraspeckle formation, miRNA synthesis and specially in transcription regulation. In addition, SFPQ play a role in the innate immune response to viruses, including DNA and RNA viruses. However, the connections between SFPQ and EMCV infection remain unclear. Here we report that the SFPQ is essential for EMCV replication. Depletion of SFPQ impairs EMCV production, while forced expression of SFPQ could promote viral replication. Mechanistically, EMCV inhibited viral RNA-mediated type I IFN and IL6 production to eliminate host antiviral immune responses. Cellular SFPQ was cleaved by the EMCV proteinase then entered the cytoplasm and interacted with other ribosomal proteins to facilitate its internal ribosome entry site (IRES)-dependent translation. Moreover, loss of SFPQ may impress host translation related gene expression and thus facilitate the EMCV replication. Altogether, our work provides a possible target for resisting EMCV or EMCV-like virus’s infection.

2019-01-10 | PXD011865 | Pride

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

| PRJNA479751 | ENA

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

| PRJNA628517 | ENA

Microarray of zebrafish (Danio rerio) sfpq-/-;Tg(mnx1:GFP) against sfpq+/+;Tg(mnx1:GFP) and sfpq+/-;Tg(mnx1:GFP) siblings at 24 hpf

Project description:Phenotypic characterisation of our zebrafish sfpq homozygous mutants revealed a restricted set of specific defects, unexpected for a protein expressed ubiquitously and involved in such general mechanisms. The CNS was prominently affected, showing brain boundary and axonal defects associated with absence of motility. To investigate a possible specificity in SFPQ functional targets by microarray RNA profiling analysis, comparing the transcriptome of the sfpq homozygous mutants with its wild type and heterozygous siblings at the earliest stage at which the phenotype is robustly recognizable.

2017-09-01 | E-MTAB-5559 | biostudies-arrayexpress

Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling

Project description:Loss of TGF-beta growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-beta resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich protein (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers, such as Hepatocellular carcinoma (HCC). In this study, we identified SFPQ as a potent suppressor of TGF-beta signaling. The ability of SFPQ to suppress TGF-beta responses depended on its prion-like domain (PrLD) that drives phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy, and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of LLPS rendered cells hypersensitive to TGF-beta responses. Together, our data reveal a unique function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-beta tumor-suppressive activity.

2023-11-16 | GSE236125 | GEO

SFPQ-ABL1 and BCR-ABL1 utilise different signalling networks to drive B-cell acute lymphoblastic leukaemia

Project description:Philadelphia-like (Ph-like) acute lymphoblastic leukaemia (ALL) is a high-risk subtype of B-cell ALL characterised by a gene expression profile resembling Philadelphia Chromosome positive ALL (Ph+ ALL) in the absence of BCR-ABL1. Tyrosine kinase activating fusions, some involving ABL1, are recurrent drivers of Ph-like ALL and are targetable with tyrosine kinase inhibitors (TKIs). We identified a rare instance of SFPQ-ABL1 in a child with Ph-like ALL. SFPQ-ABL1 expressed in cytokine-dependent cell lines was sufficient to transform cells which were sensitive to ABL1-targeting TKIs. In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival through upregulation of Mcl-1 and Bcl-xL. SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.

2022-05-20 | PXD028925 | Pride

SFPQ-ABL1 and BCR-ABL1 utilise different signalling networks to drive B-cell acute lymphoblastic leukaemia

Project description:Purpose: We identified a rare instance of the SFPQ-ABL1 in a child with Ph-like ALL. The overall purpose of this study was to compare the structure and function of the SFPQ-ABL1 fusion to the well characterised BCR-ABL1 fusion. We used phosphoproteomics, transcriptomics and functional assays to determine the transforming capacity, subcellular localisation, and signalling networks of these two fusions. Given the known function of SFPQ in mRNA splicing, transcriptomic analysis was performed to analyse the effect of BCR-ABL1 or SFPQ-ABL1 expression on gene splicing. Methods: mRNA profiles of Ba/F3 cells expressing BCR-ABL1, SFPQ-ABL1, and empty vector control (MSCV) were generated by deep sequencing, in four biologically independent cell lines, using Illumina GAIIx. The sequences were aligned by subread and quantified by featureCounts. Results: In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. We identified no difference in overall splicing between cells expressing BCR-ABL1 and SFPQ-ABL1. Conclusions: SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.

2021-10-15 | GSE185860 | GEO

SFPQ promotes an oncogenic transcriptomic state in melanoma

Project description:Analysis of SFPQ interactome in primary melanocytes and melanoma cells. Results provide insight into the oncogenic reprogamming of SFPQ-RNA interactome and especially the interactions with key melanoma-associated coding transcripts.

2021-06-30 | GSE171291 | GEO

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