Dataset Information

Context-dependent phosphorylation of CSDE1 drives interactions with ribosomes

ABSTRACT: The RNA-binding protein CSDE1 is a key regulator of mRNA stability and translation in a broad spectrum of biological processes. We have previously shown that CSDE1 functions as an oncoprotein promoting invasion and metastasis in melanoma, whereas it behaves as a tumour suppressor promoting cellular senescence in squamous cell carcinoma. The reasons underlying these context-specific behaviours are unknown. To identify melanoma-specific vulnerabilities, we have compared CSDE1 protein isoforms and post-translational modifications in melanoma cells and keratinocytes, and in melanocytic cells of different tumorigenic potential. By combining long-read Nanopore sequencing with two-dimensional gel electrophoresis and transcriptome analysis, we identify one major isoform expressed in melanoma cells and patient samples. This isoform is phosphorylated early during cellular transformation, correlating with changes in its subcellular localization. We provide extensive interactome analysis of mammalian CSDE1, showing increased interactions with ribosomes in melanoma cells compared to healthy melanocytes. Importantly, interactions of CSDE1 with the ribosome are promoted by CSDE1 phosphorylation. Our data uncover a specific feature of melanoma cells that could be harnessed for therapeutic intervention

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte

DISEASE(S): Melanoma

SUBMITTER: Cristina Chiva

LAB HEAD: Fátima Gebauer

PROVIDER: PXD062774 | Pride | 2025-09-10

REPOSITORIES: Pride

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Context-dependent phosphorylation of CSDE1 drives interactions with ribosomes.

Ciocia Annagiulia A Guitart Tanit T Mestre-Farràs Neus N Nogales Adrià A Milenkovic Ivan I Coll Olga O Medina Rebeca R Chiva Cristina C Sabidò Eduard E Novoa Eva Maria EM Gebauer Fátima F

RNA (New York, N.Y.) 20250829

The RNA-binding protein CSDE1 is a key regulator of mRNA stability and translation in a broad spectrum of biological processes. We have previously shown that CSDE1 functions as an oncoprotein promoting invasion and metastasis in melanoma, whereas it behaves as a tumour suppressor promoting cellular senescence in squamous cell carcinoma. The reasons underlying these context-specific behaviours are unknown. To identify melanoma-specific vulnerabilities, we have compared CSDE1 protein isoforms and ...[more]

PMID: 40883018

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Project description:We previously identified the induction of growth arrest with phenotypic characteristics of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters namely TPA (12-O-tetradecanoylphorbol-13-acetate) and PEP008 (20-O-acetyl-ingenol-3-angelate) in sensitive and resistant cell lines derived from melanoma, breast cancer and colon cancer. We showed the diterpene esters to induce senescence-like growth arrest in the sensitive cells at 100-1000 ng/ml. Use of the pan-PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling revealed that pivotal genes involved in DNA synthesis and cell cycle control were down-regulated by treatment in all three sensitive solid tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21WAF1/CIP1 and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Although activation of extracellular signal-related kinase (ERK) 1/2 by the diterpene esters occurred in both sensitive and resistant cell lines, the HRASLS3 type II tumor suppressor, which appears to have a role in MAPK pathway suppression, was constitutively elevated in the resistant cell lines compared to their sensitive counterparts. Together, these results demonstrate the ability of the PKC activating drugs TPA and PEP008 to induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types through a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a range of solid tumors. Experiment Overall Design: We analyzed the transcriptional profiles of the diterpene ester sensitive cell lines MCF7, COLO-205 and SK-MEL-5 following treatment with PEP008 using full genome expression profiling (Affymetrix, U133 Plus 2.0). Cells were treated for 24 h and 24 h plus 72 h recovery with 1000 ng/ml of the drug, before harvesting RNA for analysis. From the cell growth assays, all three cell lines demonstrated permanent growth arrest with diterpene ester treatments at the 1000 ng/ml dose. Mock controls were treated with solvent alone for 24 h. SK-MEL-5 cells were also treated with 1000 ng/ml TPA for 24 h.

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