Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression.
Transfer RNAs (tRNAs) are primarily viewed as static contributors to gene expression. By developing a high-throughput tRNA profiling method, we find that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity. Through loss-of-function, gain-of-function, and clinical-association studies, we implicate tRNAGluUUC and tRNAArgCCG as promoters of breast cancer metastasis. Upregulation of these tRNAs enhances stability and ribosome occupancy of transcripts enriched for their cognate codons. Specifically, tRNAGluUUC promotes metastatic progression by directly enhancing EXOSC2 expression and enhancing GRIPAP1-constituting an "inducible" pathway driven by a tRNA. The cellular proteomic shift toward a pro-metastatic state mirrors global tRNA shifts, allowing for cell-state and cell-type transgene expression optimization through codon content quantification. TRNA modulation represents a mechanism by which cells achieve altered expression of specific transcripts and proteins. TRNAs are thus dynamic regulators of gene expression and the tRNA codon landscape can causally and specifically impact disease progression.
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: hgoodarzi@mail.rockefeller.edu.
Hani
H
Goodarzi
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Hoang C B
HCB
Nguyen
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Steven
S
Zhang
Proteome Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Brian D
BD
Dill
Proteome Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Henrik
H
Molina
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: stavazoie@mail.rockefeller.edu.
Sohail F
SF
Tavazoie
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003062:Codon; D018450:Disease Progression; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D061206:Neoplasm Micrometastasis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012343:RNA, Transfer / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid; D012270:Ribosomes / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D003062:Codon; C571394:EXOSC2 protein, human; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D012343:RNA, Transfer; D063326:Exosome Multienzyme Ribonuclease Complex