MYC Dosage Compensation is Mediated by miRNA-Transcription Factor Interactions in Aneuploid Cancer

Cancer complexity is consequence of genomic instability leading to aneuploidy. We hypothesize that dosage compensation of critical genes arise from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We developed a computational platform to identify a network of miRNAs and transcription factors interacting with candidate dosage-compensated genes using NCI-60 multi-omic data. We next constructed a mathematical model where the property of dosage compensation emerged for MYC and STAT3 and was dependent on the kinetic parameters of their feedback and feed-forward interactions with four miRNAs. We developed a genetic tug-of-war approach by overexpressing an exogenous MYC sequence to experimentally validate MYC dosage compensation circuits as demonstrated by the over-expression of the three microRNAs involved and the respective down-regulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. The study of TCGA breast cancer patient data indicated that MYC dosage compensation could lead to lower patient survival, highlighting the potential of targeting gene dosage compensation to prevent aneuploid cancer progression.