3' UTR shortening of ceRNA genes disrupts miRNA binding, freeing miRNAs to repress tumor suppressors.
Major finding: 3' UTR shortening of ceRNA genes disrupts miRNA binding, freeing miRNAs to repress tumor suppressors.
Mechanism: 3' UTR shortening of the ceRNA gene EPS15 deletes 4 miRNA binding sites that overlap with PTEN.
Impact: 3' UTR shortening promotes tumorigenesis via tumor suppressor repression instead of oncogene induction.
Alternative polyadenylation leads to widespread shortening of mRNA 3' untranslated regions (UTR) that can promote tumorigenesis in vivo. The 3' UTR shortening is thought to result in loss of regions required for miRNA-mediated repression, thereby inducing expression of proto-oncogenes in cis. However, this mechanism is not sufficient to explain the observed effects of 3' UTR shortening in tumorigenesis. Park, Ji, and colleagues found that 3' UTR shortening is enriched at transcripts predicted to act as competing endogenous RNAs (ceRNA) for tumor suppressor genes, leading to the hypothesis that 3' UTR shortening might prevent miRNA binding and sequestration, freeing miRNAs to repress their ceRNA partners (including tumor suppressors) in trans to promote tumorigenesis. To test this hypothesis, ceRNA global regulatory networks in ER+ breast tumors were reconstructed using data from The Cancer Genome Atlas. Overall, 427 genes with recurrent 3' UTR shortening were identified including the ceRNA gene EPS15, which underwent shortening in 23 of 68 tumors (33.8%). EPS15 has 4 miRNA binding sites that overlap with the tumor suppressor PTEN, and 3' UTR shortening resulted in loss of the miRNA sites, preventing it from competing with PTEN miRNAs, thereby facilitating PTEN silencing. The large majority of ceRNAs downregulated in tumors were in genes affected by 3' UTR shortening, and the 3' UTR shortening ceRNA hub genes were enriched for tumor suppressors, but not oncogenes, suggesting that 3' UTR shortening represses tumor suppressor genes in trans, as with EPS15 and PTEN, instead of by inducing oncogene expression in cis. Consistent with these findings, depletion of the master regulator of 3' UTR shortening, NUDT21, repressed tumor suppressor genes including PHF6 and LARP1 in trans in a miRNA-dependent manner. Collectively, these findings reveal a mechanism by which 3' UTR shortening can repress tumor suppressor genes in trans by disrupting ceRNA cross-talk.
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