Chromosome 1q amplification perturbs a ceRNA network to promote melanoma metastasis

Abstract

SUMMARYDeregulated gene expression through epigenetic, transcriptional, and copy number alterations is a major driver of melanoma progression and metastasis. In addition to serving as blueprints for translation, some mRNAs post-transcriptionally regulate gene expression by competitively sequestering miRNAs they share with other targets. Here we report that such mRNAs, termed competitive endogenous RNAs (ceRNAs), contribute to melanoma progression and metastasis. ceRNA predictions identified multiple candidate genes on chromosome 1q, which is recurrently amplified in melanoma. Genetic studies reveal that three of these mRNAs, CEP170, NUCKS1, and ZC3H11A, promote melanoma migration, invasion, and metastasis in a protein coding-independent and miRNA binding site-dependent manner. Interestingly, CEP170, NUCKS1, and ZC3H11A cooperate to elicit oncogenic effects by collectively impairing the tumor suppressor activity of 8 miRNAs on several pro-metastatic target genes. Finally, this complex chromosome 1q ceRNA network is evident in other cancer types, suggesting ceRNA network deregulation is a common driver of cancer progression.