tRF-21LeuTAA Promotes Oxidative Stress by Altering Glutathione Metabolic Enzymes to Support Prostate Cancer Progression

Abstract Transfer RNA–derived fragments (tRF) are a class of small noncoding RNAs that have recently been implicated in various physiologic and pathologic processes, including tumor development and progression. Identification of the roles of tRFs in cancer could provide insights into tumor biology and treatment strategies. In this study, we found that tRF-21LeuTAA (tRF-21) supported the progression of prostate cancer by regulating glutathione metabolic enzymes and promoting reactive oxygen species (ROS) accumulation. Nuclear tRF-21 upregulated leucyl aminopeptidase 3 (LAP3) by binding to its promoter and recruiting H3K27ac acetyltransferase P300 and transcription factor STAT1. The increased cystine–glycine dipeptidase activity of LAP3 led to increased degradation of the antioxidant glutathione. Alternatively, cytoplasmic tRF-21 suppressed glutathione S-transferase mu 3 by repressing its mRNA posttranscriptionally, which further elevated ROS by decreasing scavenger glutathione S-transferase activity. The accumulation of intracellular ROS downstream of tRF-21–mediated alterations in LAP3 and glutathione S-transferase mu 3 resulted in AKT activation. Overexpression of tRF-21 promoted the proliferation and migration of prostate cancer cells, formation of spheroids, and initiation and growth of tumors in a xenograft model. In patients, elevated tRF-21 and LAP3 levels were associated with unfavorable survival outcomes. The regulatory circuitry revealed in the present study may represent potential therapeutic targets for prostate cancer as well as various malignancies with tRF-21 overexpression. Significance: tRF-21 promotes tumor development by disrupting key metabolic, epigenetic, transcriptional, and post-transcriptional processes that converge on increased oxidative stress, suggesting that targeting this axis may benefit malignancies with elevated tRF-21.