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Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1

ABSTRACT: Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83678 | GEO | 2017/12/22

SECONDARY ACCESSION(S): PRJNA326686

REPOSITORIES: GEO

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Silencing RNA-binding protein CELF1 inhibits tumor growth and alters gene expression in oral squamous cell carcinoma

Project description:RNA-binding proteins (RBPs) are critical regulators of gene expression, but only a small fraction have been studied for their role in malignancy. Here we report a systematic analysis of RBP CUGBP Elav-Like Family member 1 (CELF1 alias CUGBP1) roles in mRNA alternative splicing, translation and turnover in oral cancer cells. CELF1 is overexpressed in carcinogen-induced oral cancer tumorigenesis mouse model and specific inhibition of CELF1 reduces tumor growth in vivo. Deep transcriptomic analysis revealed that hundreds of mRNAs were differentially regulated as a function of CELF1 expression in oral cancer cells. More importantly, the presence of CELF1 promoted alternative splicing of several target mRNAs which are known to be involved in various cancer biological processes. Using a pulse SILAC-based quantitative proteomic approach, we observed hundreds of proteins whose translation was controlled by CELF1 and those altered proteins were implicated in malignancy. Altogether, these data provided a comprehensive view of the CELF1 mRNA regulatory network in OSCC and suggests that CELF1 is a viable target for therapeutic intervention. Significance Post-transcriptional mechanisms that regulate cancer cells which are believed to constitute the driving force of many malignancies are poorly understood. We show that oral squamous cell carcinoma (OSCC) emerge as a result of an over expressed RNA-binding protein CELF1, a protein implicated in mRNA turnover, alternative splicing and translation. The resulting mRNA expression repertoire regulates networks of genes whose expression changes regulate oral cancer pathogenesis. Inhibition of CELF1 mitigated OSCC tumor-forming capacity and offers an attractive therapeutic option for oral malignancies. Transcriptomic analysis of UMSCC-74B oral cancer cells as a function of CELF1 protein expression.

2015-09-01 | E-GEOD-57254 | biostudies-arrayexpress

Silencing RNA-binding protein CELF1 inhibits tumor growth and alters gene expression in oral squamous cell carcinoma

2015-09-01 | GSE57254 | GEO

Quantitative proteomics of CELF1-silenced human melanoma cell lines

Project description:CELF1 was silenced in two human melanoma cell lines (SKMEL-103 and UACC-62, indicated as 9M and 17M, respectively) using short hairpin RNA (tag 114). As control scrambled non targeting shControl transduced cell were used (tag 115).

2017-12-21 | PXD003112 | Pride

Regulation of the mouse heart transcriptome by Celf1

Project description:The CUG-BP and ETR-3-like factor 1 (Celf1) RNA binding protein plays an important role in heart and muscle development, and is over-expressed in the disease myotonic dystrophy. Celf1 has known roles in regulation of RNA splicing, RNA stability, and protein translation. To identify transcriptome-wide targets of the Celf1 protein in heart, we performed RNA-Seq of polyA+ RNA from mice inducibly expressing Celf1 in the heart. Mice were engineered to express the reverse tetracycline trans-activator (rtTA) from a heart-specific alpha myosin heavy chain promoter, and an N-terminal Flag-tagged version of the LYLQ isoform of human Celf1 from a tet-inducible promoter. Mice were fed doxycycline to induce Celf1 expression in heart, and hearts were harvested from 3 mice each at 12 hour, 24 hour, 72 hour, and 7 day time points. To account for potential doxycycline-dependent effects, control mice were fed doxycycline for 72 hours but these mice did not contain the tet-inducible Celf1 cassette. In total, 15 hearts were analyzed by RNA-Seq.

2014-04-01 | E-GEOD-56185 | biostudies-arrayexpress

CELF1 upregulates MMP gene expression to regulate cataract development

Project description:As a multifunctional RBP, CELF1 is known to preferentially binds to GU-rich elements (GREs) predominantly located in 3’ untranslated regions(UTRs) of target mRNA to regulate various post-transcriptional process. However, the targeted genes that regulated by CELF1 during cataractogenesis remains unknown. In present study,the function of CELF1 in SRA01/04 cells was investigated with CELF1 overexpression, the expression of MMPs was regulated by CELF1.

2022-03-23 | GSE153022 | GEO

Celf1 and Postnatal Lens Microarray

Project description:Celf1 germline or conditional deletion mouse mutants exhibit fully penetrant lens defects including cataract. To gain insight into gene expression changes underlying these lens defects, microarray comparison was performed for lenses obtained from control and Celf1 conditional deletion mutant mice.

2023-02-18 | GSE225303 | GEO

Regulation of the mouse heart transcriptome by Celf1

2014-04-01 | GSE56185 | GEO

Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1

Project description:The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up-regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated.

2016-10-22 | GSE85646 | GEO

Transcriptomic analysis of HeLa cells depleted in CELF1, ELAVL1, and both

Project description:ELAVL1 and CELF1 are two RNA-binding proteins involved in alternative splicing control. To address their functional relationships, we identify the differentially spliced mRNAs upon depletion of CELF1, ELAVL1, or both. These proteins control similar sets of genes with similar consequences on exon inclusion or skipping. The magnitude of the effect of the double depletion equals the sum of the magnitudes of the individual depletions, showing that CELF1 and ELAVL1 additively control their target RNAs. CELF1 and ELAVL1 regulated splicing events include ACSL4, WNK1, CD44, MICAL3, and JDP2. Using FRET, we find that CELF1 and ELAVL1 directly interact in cell nuclei. We demonstrate that the combined levels of CELF1 and ELAVL1 is a valuable biomarker in breast cancer, while their levels bring very limited information when taken individually. A “co-RNA splicing map” of CELF1 and ELAVL1 shows they repress alternative splice sites when bound nearby, but activate them when bound further away. Together, these data point to strong functional interactions between CELF1 and ELAVL1 to control alternative splicing with significant impacts in human pathology.

2021-08-01 | GSE118981 | GEO

A conserved RNA-binding protein Celf1 controls cell differentiation in vertebrate eye development

Project description:Celf1 germline or conditional deletion mouse mutants exhibit fully penetrant lens defects including cataract. To gain insight into gene expression changes underlying these lens defects, microarray comparison was performed for lenses obtained from wild-type and Celf1 conditional deletion mutant mice. At ±2.0 fold-change cut-off (p<0.05), 102 genes were identified to be differentially expressed in Celf1 conditional mutant lenses

2018-05-11 | GSE101393 | GEO

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