Abstract A41: A single let-7 microRNA bypasses LIN28-mediated repression

The let-7 miRNA family members are small non-coding RNAs that function as tumor suppressors and are frequently down-regulated in many different types of cancers upon reactivation of LIN28 oncogenes. Mammalian genomes contain twelve let-7 isoforms that suppress expression of a common set of target mRNAs comprising key oncogenes and mitotic regulators. LIN28 proteins selectively block let-7 biogenesis postranscriptionally. The current model for coordinate let-7 repression involves the LIN28 cold shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in cancer. Citation Format: Robinson Triboulet, Mehdi Pirouz, Richard I. Gregory. A single let-7 microRNA bypasses LIN28-mediated repression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A41.