MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer
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| Autores: | , , , , , , , , , , , , , , , , |
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| Formato: | artículo original |
| Fecha de Publicación: | 2021 |
| Descripción: | We hypothesize that dosage compensation of critical genes arises from systems- level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interac- tion network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for MYC and was dependent on the kinetic pa- rameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overex- press an exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpres- sion or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. Finally, we identified negative correlation of MYC dosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneu- ploid cancer progression. |
| País: | Kérwá |
| Institución: | Universidad de Costa Rica |
| Repositorio: | Kérwá |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:kerwa.ucr.ac.cr:10669/86990 |
| Acceso en línea: | https://www.cell.com/iscience/home https://hdl.handle.net/10669/86990 https://doi.org/10.1016/j.isci.2021.103407 |
| Palabra clave: | miRNA Myc Dosage compensation cancer Transcription factors aneuploidy |