tRF-3021a Supports Invasiveness, Apoptosis Resistance, and Global Protein Synthesis in Cancer Cell Lines

tRNA-derived fragments (tRFs) are a relatively recently discovered class of small RNAs implicated in gene-regulatory processes in diverse biological contexts but there have been very few reports of a clear phenotypic role of these small RNAs in cancer progression. To select tRFs that should receive priority for mechanistic experiments, we analyzed small RNA-seq data from The Cancer Genome Atlas (TCGA) and found that high expression of three 3' tRFs (tRF-3a), tRF-3009a, tRF-3021a or tRF-3030a, is significantly associated with poor overall survival in low-grade glioma (LGG). In glioblastoma cells, tRF-3009a, tRF-3021a and tRF-3030a enhance cell invasion and migration but tRF-3021a was uniquely required for cell proliferation and suppression of apoptosis. Interestingly, tRF-3021a knockdown decreases global protein synthesis prior to and independent of apoptosis in a number of cancer cell lines, both from and outside the glioblastoma lineage. RNA-seq reveals that the results cannot be explained by microRNA-like functions of tRF-3021a. These data indicate that tRF-3021a supports cancer cell survival and particularly protein synthesis while promoting cellular invasion and migration and suggests that strategies to downregulate this short RNA could be a potential therapeutic approach in cancers. ImplicationtRF-3021a promotes malignant cell phenotypes, sustains global protein synthesis and prevents spontaneous apoptosis, motivating efforts to evaluate it as a biomarker and therapeutic target.