3?-UTR Shortening Represses Tumor Suppressor Genes in Trans by Disrupting CeRNA Crosstalk

• Activity Number: 99 - Single Cell Sequencing and Cancer Genomics
• Type: Invited
• Date/Time: Monday, July 30, 2018 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Wei Li*
• Companies: Baylor College of Medicine
• Keywords: oncogenes; tumor suppressor genes; alternative polyadenylation; cancer

Abstract

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.