FUT8 is a critical driver of prostate tumour growth and can be targeted using fucosylation inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1176518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31091133.fastq.gz | Fastqsanger.gz | |||
| SRR31091134.fastq.gz | Fastqsanger.gz | |||
| SRR31091135.fastq.gz | Fastqsanger.gz | |||
| SRR31091136.fastq.gz | Fastqsanger.gz | |||
| SRR31091137.fastq.gz | Fastqsanger.gz |
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Project description:To identify signalling pathways altered by FUT8 in prostate cancer cells, we established luciferase-tagged CWR22Rv1 stable cell lines in which FUT8 was overexpressed (OE) and luciferase-tagged PC3 cell lines in which FUT8 was knocked down (KD). We then performed differential gene expression, Gene Ontology and GSEA analyses using data obtained from RNA-seq of the control and FUT8 overexpression, and the control and knockdown cell lines.
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Project description:Natural Killer (NK) cell development and effector function requires context-dependent signalling via numerous receptors including the IL-15 receptor. The modulation of receptor signalling can be regulated by the post-translational modifications affecting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). To investigate core fucosylation in NK cell biology, we generated mice lacking FUT8 in NK cells (Fut8fl/flNcr1cre/+). Loss of core fucose resulted in pronounced NK lymphopenia in Fut8fl/flNcr1cre/+ mice associated with a reduction in IL-15 receptor expression and loss of in vivo proliferation. Inhibition of intrinsic apoptosis pathways could not overcome compromised IL-15 receptor signalling to rescue FUT8-null NK cell development delineating the contribution of proliferation to NK cell homeostasis. Surprisingly, loss of core fucose enhanced NK cell expansion following viral infection and this was associated with upregulation of IL-2Rα following pro-inflammatory cytokine exposure and enhanced IL-2-mediated proliferation. Lastly, loss of FUT8 activity impaired TGFBR2 expression and immunosuppressive effects of TGF-β on NK cells. Taken together, we have identified fucosyltransferase 8 as a key modulator of NK cell development and function by regulating IL-15 receptor responsiveness.
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Project description:Overexpression of fucosyltransferase 8 (FUT8) is found in many cancers including liver, ovarian, thyroid, colorectal and non-small cell lung cancers. Unlike other FUTs which are functionally redundant, FUT8 is the only enzyme responsible for the alpha1,6-linked fucosylation (core fucosylation) by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions, such as EGFR, TGF beta receptor and integrins. To understand the downstream molecular events in response to the global alteration of core fucosylation during cancer progression, microarray analysis was employed to profile the changes in gene expression following FUT8 silencing. The genes significantly (2-fold, P<0.01) changed in CL1-5/shFUT8 cells were selected for functional annotations using a Gene Ontology database. The result revealed that many genes involved in cell adhesion, motility, growth, angiogenesis, and inflammation were under the control of core fucosylation. In this experiment, the gene expression profile of two stable FUT8 knockdown clones of CL1-5 cells, CL1-5/shFUT8-1 and CL1-5/shFUT8-2, were compare with CL1-5/Control cells. A total of eight samples were analyzed, including four CL1-5/Control vs. CL1-5/shFUT8-1 and four CL1-5/Control vs. C1-5/shFUT8-2. The biological replicates for each cell lines were four.
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Project description:Overexpression of fucosyltransferase 8 (FUT8) is found in many cancers including liver, ovarian, thyroid, colorectal and non-small cell lung cancers. Unlike other FUTs which are functionally redundant, FUT8 is the only enzyme responsible for the alpha1,6-linked fucosylation (core fucosylation) by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions, such as EGFR, TGF beta receptor and integrins. To understand the downstream molecular events in response to the global alteration of core fucosylation during cancer progression, microarray analysis was employed to profile the changes in gene expression following FUT8 silencing. The genes significantly (2-fold, P<0.01) changed in CL1-5/shFUT8 cells were selected for functional annotations using a Gene Ontology database. The result revealed that many genes involved in cell adhesion, motility, growth, angiogenesis, and inflammation were under the control of core fucosylation.
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Project description:Differentiation therapy with all-trans retinoic acid (ATRA) is well established for acute promyelocytic leukemia (APL). However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we challenged glycosylation inhibitor to obtain better efficiency than ATRA alone. As a result, we found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) with ATRA have profound effect for differentiation, shown by expression changes of differentiation markers CD11b, CD11c, with significant morphological change in NB4 and HL-60 cells. From lectin blot assay, we found that ATRA or 6AF alone could decrease core fucosylation, the combination of these two agents efficiently decreases the expression of core fucosylation. To reveal molecular mechanisms to reveal 6AF effect for ATRA induced differentiation, we next performed microarray analysis using NB4 cells. From pathway analysis using DAVID software, we found that C-type lectin receptor (CLR) signaling pathway was enriched as high significance. From real time PCR analysis, using NB4 and HL-60 cells, FcRI, CLEC6A, CASP1, IL-1, EGR2/3, the components of CLR, and Akt, were indeed upregulated by 6AF in ATRA induced differentiation. These suggest that the involvement of CLR signaling pathway in 6AF effect of ATRA induced differentiation.
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Project description:Prostate cancer is the most commonly diagnosed oncogenic malignancy in men worldwide, resulting in almost 30,000 cancer-related deaths in the United States each year. Wider examination of aberrant glycosylation in prostate cancer has revealed increased expression of the glycotransferase involved in core fucosylation, (1,6)fucosyltranferase (FUT8) associating with aggressive (AG) prostate cancer and castration-resistance, with functional analyses revealing FUT8 impacting cell motility and invasiveness in prostate cancer cells. Exosomes are extracellular microvesicles (30-150 nm) that are involved in in both proximal and distal intercellular communication via the transport of proteins and nucleic acids (mRNA, miRNA, and DNA). To gain insight into the impact of increased cellular FUT8 expression on exosome biogenesis and protein cargo profiles in prostate cancer, we paired Nanoparticle Tracking Analysis (NTA) and stable isotope labelling with amino acids in cell culture (SILAC) quantitative proteomics.
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Project description:Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Among these responses, temporary anorexia associated with an infection is often beneficial. It poses, however, a problem for the trillions of microbes residing in the gastrointestinal tract, as they also experience reduced substrate availability. We hypothesized that under anorectic conditions caused by infection, the host might activate protective mechanisms to support the gut microbiota during the acute phase of the disease. Here, we report that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α1,2-fucosylation of the small intestine epithelial cells (IEC). The process requires sensing of TLR agonists and production of IL-23 by dendritic cells, activation of innate lymphoid cells and expression of α1,2-Fucosyltransferase-2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is utilized by microbiota, as shown using reporter bacteria and by transcriptional profiling of the gut microbiome. Fucosylation also reduces the expression of bacterial virulence genes within the commensal gut microbiome and improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host-microbial interactions during pathogen-induced stress. RNA-Seq analysis of the murine gut microbiome following LPS exposure. Fut2-/- (B6.129X1-Fut2tm1Sdo/J) mice were backcrossed greater than 7 generations to BALB/c. Fut2-/- (KO) and Fut2+/- (Het) animals were analyzed.
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