Abstract:
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Widespread mRNA 3?-UTR shortening through alternative polyadenylation (APA) promotes tumor growth in vivo. A prevailing hypothesis is that it induces proto-oncogene in cis through escaping microRNA-mediated repression. Here we show that shortened 3?-UTRs in breast cancer patient samples are strongly associated with repression of tumor suppressor genes enriched in competing endogenous RNAs (ceRNAs). Our model-based analysis of the trans effect of 3?-UTR shortening (MAT3UTR) reveals its dominant role in altering ceRNA expression. MAT3UTR predicts many trans-targets of 3?-UTR shortening, including PTEN, a crucial tumor suppressor gene involved in ceRNA crosstalk with nine 3'-UTR shortening genes, including EPS15 and NFIA. Importantly, knockdown of NUDT21 (also known as CFIm25), a master 3?-UTR shortening regulator, can direct the release of microRNAs to repress the tumor suppressor genes, such as PHF6 and LARP1 in trans in a miRNA dependent manner. Together, our big data analysis followed by functional validation suggests that the major role of 3?-UTR shortening in tumorigenesis might be to repress tumor suppressor genes in trans, rather than induce proto-oncogenes in cis.
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