MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

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 mode...

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Detalles Bibliográficos
Autores: Acón, Man Sai, Geiß, Carsten, Torres Calvo, Jorge, Bravo Estupiñan, Diana, Oviedo Blanco, Guillermo, Arias Arias, Jorge Luis, Rojas Matey, Luis Andres, Báez Villalobos, Edwin, Vásquez Vargas, Gloriana, Oses Vargas, Yendry, Guevara Coto, José Andrés, Segura Castillo, Andrés, Siles Canales, Francisco, Quirós Barrantes, Steve, Régnier Vigouroux, Anne, Mendes, Pedro, Mora Rodríguez, Rodrigo Antonio
Tipo de recurso: artículo
Fecha de publicación:2021
País:Costa Rica
Institución:Universidad de Costa Rica
Repositorio:Kérwá
Idioma: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
Access Level:acceso abierto
Palabra clave:miRNA
Myc
Dosage compensation
cancer
Transcription factors
aneuploidy
Descripción
Sumario: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.

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