tRNA dosage regulates lineage plasticity and therapy resistance in prostate cancer through codon bias [RNA-seq]

Using prostate cancer as a paradigm of lineage dependence, we performed unbiased small RNA sequencing and identified tRNAArg(UCU)-1 as a regulator of lineage transitions and therapy resistance. tRNAArg(UCU)-1 is both necessary and sufficient to reprogram lineage dependence which can be tuned to restore sensitivity to androgen receptor-targeted therapies.

We identify TARDBP and ZSCAN29 as DNA-binding proteins that directly engage the genomic locus of tRNAArg(UCU)-1 to regulate its expression revealing the importance of non-canonical tRNA-specific gene regulation. Mechanistically, tRNAArg(UCU)-1 controls a translational program centered on SWI/SNF chromatin remodelers, which are necessary to maintain lineage fidelity. In patients, tRNAArg(UCU)-1 is downregulated in neuroendocrine prostate cancer and its loss is associated with accelerated metastasis and poor survival.