Widespread mRNA 3′ UTR shortening through alternative polyadenylation promotes tumor growth in vivo. A prevailing hypothesis is that it induces proto-oncogene expression in cis through escaping microRNA-mediated repression. Here, a team of researchers from Baylor College of Medicine, UTMB, UTHSCH, and UT Medical School report a surprising enrichment of 3′UTR shortening among transcripts that are predicted to act as competing-endogenous RNAs (ceRNAs) for tumor-suppressor genes. Their 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 gene3 involved in ceRNA crosstalk4 with nine 3′UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3′ UTR-shortening regulator2, represses tumor-suppressor genes such as PHF6 and LARP1 in trans in a miRNA-dependent manner. Together, the results of this 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.
3′UTR shortening contributes to ceRNET disruption
a, Pearson’s correlation coefficients of 100,000 randomly selected transcript pairs with significant miRNA-binding-site overlap in breast tumors and matched normal tissues. b, The number of ceRNA pairs in breast tumor and the matched normal ceRNETs. The numbers in parentheses are normalized to the number of edges shared between tumor and normal. c, Gene expression of EPS15 (3′US gene) and PTEN (ceRNA partner) on 68 estrogen-receptor-positive (ERP) breast tumors and matched normal samples. The horizontal lines represent the mean expression values of PTEN, which is decreased in tumors (FDR = 2.1 × 10−10). d, The upper heatmap exhibits significant APA events (rows) across 68 ERP tumor/normal pairs (columns), ranked by the number of 3′US genes. The Venn diagrams show the number of ceRNA pairs in the normal and tumor ceRNET. The numbers in parentheses are normalized to the number of edges shared between tumor and normal tissues. The P value was calculated from a one-tailed Pearson’s chi-squared test.