title: Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.
abstract: Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) 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.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Goodarzi
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Xuhang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Hoang C B
authors.initials: HC
authors.lastname: Nguyen
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fish
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: stavazoie@mail.rockefeller.edu.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000494:pharmacology; D058727:RNA, Small Untranslated / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D009841:Oligonucleotides; D058727:RNA, Small Untranslated; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C477371:locked nucleic acid; D012343:RNA, Transfer