Abstract

The evolution of a cancer to an aggressive state requires altered expression of a large number of genes. How such expression states are established has been an area of intense investigation. The last decade has revealed post-transcriptional regulation of gene-expression by small non-coding RNAs to be a major mechanism by which aggressive gene expression states are established. Our lab has found that modulated expression of tissue-specific microRNAs in diverse cancer types is required for metastatic progression to occur. The use of these microRNAs as molecular probes has provided molecular and cellular insights into the biology of this disease. During our studies of metastatic cells, we have stumbled upon another class of small-RNAs that are cleavage products of transfer RNAs. We have identified a subset of such tRNA-derived fragments (tRFs) as suppressors of metastatic progression. These fragments are tumorsuppressive molecules that are generated in normal cells upon hypoxic stress but repressed in aggressive cells. These tRFs suppress growth by binding to the growth promoting RNA binding protein YBX1 . The binding of these tRFs to YBX1 reduces YBX1 binding to its native target transcripts, which encode oncogenic growth promoting proteins. These transcripts are normally stabilized by YBX1 . Their reduced binding to YBX1 leads to their degradation. Our findings reveal a previously unrecognized RNA regulatory code embedded in tRNAs and their tRF products, which mediate posttranscriptional gene regulation