Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Nat Genet. 2018 Jun;50(6):783-789. doi: 10.1038/s41588-018-0118-8. Epub 2018 May 21.
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 we report a surprising enrichment of 3'UTR shortening among transcripts that are predicted to act as competing-endogenous 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 involved in ceRNA crosstalk with nine 3'UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3' UTR-shortening regulator , 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.
通过可变多聚腺苷酸化广泛缩短 mRNA 3'UTR 促进体内肿瘤生长。一种流行的假说认为，它通过逃避 microRNA 介导的抑制作用，在顺式诱导原癌基因表达。在这里，我们报告了在被预测为肿瘤抑制基因竞争内源性 RNA（ceRNA）的转录本中，3'UTR 缩短的惊人富集。我们基于模型的 3'UTR 缩短的转位效应分析（MAT3UTR）揭示了在改变 ceRNA 表达方面的重要作用。MAT3UTR 预测了许多 3'UTR 缩短的转位靶标，包括 PTEN，这是一个关键的肿瘤抑制基因，涉及与九个 3'UTR 缩短基因（包括 EPS15 和 NFIA）的 ceRNA 串扰。3'UTR 缩短的主要调节因子 NUDT21 的敲低以 miRNA 依赖的方式在转位抑制肿瘤抑制基因，如 PHF6 和 LARP1。总之，我们分析的结果表明，3'UTR 缩短在通过破坏 ceRNA 串扰在转位抑制肿瘤抑制基因方面发挥主要作用，而不是在顺式诱导原癌基因。
