Somatic copy-number alterations (CNA) promote
cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded
proteins are considered. mRNAs can act as competitive endogenous RNAs (
ceRNA), which sponge
miRNAs to posttranscriptionally regulate gene expression in a
protein coding-independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted
melanoma progression and
metastasis at least in part through overexpression of three mRNAs with
ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced
melanoma metastasis by sequestering
tumor suppressor
miRNAs. Orthogonal genetic assays with
miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that
miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q
ceRNA-mediated
miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory
RNA network was evident in other
cancer types, suggesting chromosome 1q
ceRNA deregulation as a common driver of
cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs.
SIGNIFICANCE: The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester
tumor suppressor
microRNAs underlies the oncogenic activity of chromosome 1q gains.