miR-34a directly targets tRNA i Met precursors and affects cellular proliferation, cell cycle, and apoptosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 28; pp. 7392 - 7397
• Main Authors: Wang, Bo, Li, Dongping, Kovalchuk, Igor, Apel, Ingrid J, Chinnaiyan, Arul M, Wóycicki, Rafał K, Cantor, Charles R, Kovalchuk, Olga
• Format: Journal Article
• Language: English
• Published: United States 10.07.2018
• Subjects: Apoptosis; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; MicroRNAs - biosynthesis; MicroRNAs - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; RNA Precursors - biosynthesis; RNA Precursors - genetics; RNA Processing, Post-Transcriptional; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; RNA, Transfer, Met - biosynthesis; RNA, Transfer, Met - genetics; apoptosis; tRNAiMet; proliferation; cell cycle; miR-34a
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1703029115

It remains unknown whether microRNA (miRNA/miR) can target transfer RNA (tRNA) molecules. Here we provide evidence that miR-34a physically interacts with and functionally targets tRNA precursors in both in vitro pulldown and Argonaute 2 (AGO2) cleavage assays. We find that miR-34a suppresses breast carcinogenesis, at least in part by lowering the levels of tRNA through AGO2-mediated repression, consequently inhibiting the proliferation of breast cancer cells and inducing cell cycle arrest and apoptosis. Moreover, miR-34a expression is negatively correlated with tRNA levels in cancer cell lines. Furthermore, we find that tRNA knockdown also reduces cell proliferation while inducing cell cycle arrest and apoptosis. Conversely, ectopic expression of tRNA promotes cell proliferation, inhibits apoptosis, and accelerates the S/G2 transition. Moreover, the enforced expression of modified tRNA completely restores the phenotypic changes induced by miR-34a. Our results demonstrate that miR-34a directly targets tRNA precursors via AGO2-mediated cleavage, and that tRNA functions as an oncogene, potentially representing a target molecule for therapeutic intervention.