Characterization of synthetic lethality between MYC activation and splicing inhibition in an immortalized cell line : roles of alternative splicing
Cancer cells exhibit a synthetic lethal (SL) phenotype when Myc upregulation is combined with antitumor drugs targeting the splicing factor SF3B1. However, the molecular events and mechanisms responsible for this vulnerability remain poorly understood. We used an immortalized cell line (h-TERT RPE M...
| Autor: | |
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/690453 |
| Acceso en línea: | http://hdl.handle.net/10803/690453 |
| Access Level: | acceso embargado |
| Palabra clave: | Alternative splicing Cancer MYC Synthetic lethality Splicing inhibition Splicing alternativo Cáncer Letalidad sintética Inhibición de splicing 576 |
| Sumario: | Cancer cells exhibit a synthetic lethal (SL) phenotype when Myc upregulation is combined with antitumor drugs targeting the splicing factor SF3B1. However, the molecular events and mechanisms responsible for this vulnerability remain poorly understood. We used an immortalized cell line (h-TERT RPE MYC-ER p53KO) which allows inducible MYC activation, and the SF3B1-targeting drug Pladienolide B (PLAD B), to recreate the SL phenotype, scored in viability and clonogenic assays. Our data indicate that apoptosis is a key pathway involved in the SL phenotype. However, contrary to the proposed role of MCL1 alternative splicing as a major mediator of apoptotic effects induced by PLAD B treatment, upregulation of the pro-apoptotic mRNA isoform of MCL1 cannot explain the SL phenotype. We carried out RNA-seq analyses to identify and functionally characterize gene expression and alternative splicing changes potentially associated with the SL phenotype. Importantly, we identified a set of exons known to be essential for cancer cells that, when induced to be skipped using antisense oligonucleotides, are detrimental for cell viability and likely contribute to the SL phenotype. |
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