3' UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk

Widespread mRNA 3' UTR shortening through alternative polyadenylation(1) promotes tumor growth in vivo(2). A prevailing hypothesis is that it induces proto-oncogene expression in cis through escaping microRNA-mediated repression. Here we report a surprising enrichment of 3' UTR shortening among transcripts that are predicted to act as competingendogenous RNAs (ceRNAs) for tumor-suppressor genes. Our model-based analysis of the trans effect of 3' UTR shortening (MAT3UTR) reveals a significant role in altering ceRNA expression. MAT3UTR predicts many trans-targets of 3' UTR shortening, including PTEN, a crucial tumor-suppressor gene(3) involved in ceRNA crosstalk(4) with nine 3' UTRshortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3' UTR-shortening regulator(2), represses tumor-suppressor genes such as PHF6 and LARP1 in trans in a miRNA-dependent manner. Together, the results of our analysis suggest a major role of 3' UTR shortening in repressing tumor-suppressor genes in trans by disrupting ceRNA crosstalk, rather than inducing proto-oncogenes in cis.