Editors' ChoiceCancer

Limiting metastasis with tRNA fragments

Sci. Signal.  26 May 2015:
Vol. 8, Issue 378, pp. ec136
DOI: 10.1126/scisignal.aac6061

Transfer RNA-derived RNA fragments (tRFs) belong to a class of short noncoding RNAs and are generated by processing of tRNAs by Dicer, RNase Z, and ribonucleases. Some tRFs are constitutively produced, and some are induced by cellular stress, such as hypoxia. Goodarzi et al. investigated the role of hypoxia-induced tRFs in cancer progression with next-generation small RNA (sRNA) sequencing and biochemical, molecular, and cellular phenotypic analysis. Hypoxia increased tRF abundance in a breast cancer cell line (MDA-parental); less induction occurred in a highly metastatic subpopulation of these cells (MDA-LM2). Sequence analysis of the tRNAs with hypoxia-induced fragmentation in the MDA-parental cells revealed enrichment of a common linear motif. A biotinylated oligonucleotide of this linear motif interacted with YBX1 (nuclease-sensitive element-binding protein 1). Cross-linking immunoprecipitation sequencing (CLIP-seq) of RNAs that coprecipitated with YBX1 showed that YBX1 also bound to oncogenic transcripts primarily at the 3ʹ untranslated region. Introduction of synthetic tRF mimetics into cells reduced the interaction of YBX1 with oncogenic transcripts, suggesting competition between the transcripts and tRFs for YBX1. Whole-genome transcript stability analysis indicated that the unbound oncogenic transcripts were degraded. MDA-parental cells transfected with synthetic antisense locked-nucleic acids (LNAs) that targeted the tRFs to block their interaction with YBX1 exhibited significantly enhanced invasive capacity into Matrigel, whereas transfection of tRF mimetics into MDA-LM2 cells reduced invasion in this assay. Compared with lung colonies that formed when the MDA-parental cells were injected into mice, increased lung colonization occurred with MDA-parental cells expressing the inhibitory antisense LNAs. In contrast, compared with the lung colonies formed by injection of MDA-LM2, injection of MDA-LM2 cells expressing the tRF mimetics resulted in reduced lung metastases. These findings identify another form of noncoding RNA as important in cancer progression.

H. Goodarzi , X. Lui, H.C. B. Nguyen, S. Zhang , L. Fish, S. F. Tavazoie, Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell. 161, 790–802 (2015). [PubMed]