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

ManSai Acón; Carsten Geiß; Jorge Torres-Calvo; Diana Bravo-Estupiñan; Guillermo Oviedo; Jorge L Arias-Arias; Luis A Rojas-Matey; Baez Edwin; Gloriana Vásquez-Vargas; Yendry Oses-Vargas; José Guevara-Coto; Andrés Segura-Castillo; Francisco Siles-Canales; Steve Quirós-Barrantes; Anne Régnier-Vigouroux; Pedro Mendes; Rodrigo Mora-Rodríguez

doi:10.1016/j.isci.2021.103407

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

iScience. 2021 Nov 8;24(12):103407. doi: 10.1016/j.isci.2021.103407. eCollection 2021 Dec 17.

Authors

ManSai Acón^{1

2}, Carsten Geiß³, Jorge Torres-Calvo^{1

2}, Diana Bravo-Estupiñan^{1

4}, Guillermo Oviedo^{1

2}, Jorge L Arias-Arias¹, Luis A Rojas-Matey², Baez Edwin^{1

2}, Gloriana Vásquez-Vargas¹, Yendry Oses-Vargas¹, José Guevara-Coto⁵, Andrés Segura-Castillo⁶, Francisco Siles-Canales^{7

8}, Steve Quirós-Barrantes^{1

8}, Anne Régnier-Vigouroux³, Pedro Mendes⁹, Rodrigo Mora-Rodríguez^{1

2

8

3}

Affiliations

¹ Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica.
² Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica.
³ Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University, 55128 Mainz, Germany.
⁴ Ph.D. Program in Sciences, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica.
⁵ School of Computer Sciences and Informatics (ECCI), University of Costa Rica, San Jose Costa Rica, 11501-2060 San José, Costa Rica.
⁶ Laboratorio de Investigación e Innovación Tecnológica, Universidad Estatal a Distancia (UNED), 474-2050 San José, Costa Rica.
⁷ Pattern Recognition and Intelligent Systems Laboratory, Department of Electrical Engineering, Universidad de Costa Rica, 11501-2060 San José, Costa Rica.
⁸ DC Lab, Lab of Surgery and Cancer, University of Costa Rica, 11501-2060 San José, Costa Rica.
⁹ Center for Cell Analysis and Modeling and Department of Cell Biology, University of Connecticut School of Medicine, Farmington, 06030 CT, USA.

Abstract

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 interaction network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for MYC and was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overexpress an exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpression 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 aneuploid cancer progression.

Keywords: Bioinformatics; Mathematical biosciences; Systems biology.

Grants and funding

R24 GM137787/GM/NIGMS NIH HHS/United States