Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement

•Hypoxic stress induces the production of tRNA-derived fragments (tRFs)•This class of tRFs suppresses the development of breast cancer metastasis•tRFs bind to oncogenic RNA-binding protein YBX1, displacing pro-oncogenic transcripts•Highly metastatic cells blunt the induction of the tRFs during hypoxia

SummaryUpon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs). We identify a novel class of tRFs derived from tRNAGlu, tRNAAsp, tRNAGly, and tRNATyr that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3′ untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.

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