tRNA dosage regulates lineage dependency and resistance in prostate cancer.

Abstract

Lineage plasticity underlies therapeutic resistance in cancer1,2, yet the translational mechanisms that enable this phenotypic flexibility remain largely unknown. Here using prostate cancer as a model of lineage dependence, we performed unbiased small RNA sequencing and identified tRNA1Arg(UCU) as a regulator of lineage transitions and therapy resistance. tRNA1Arg(UCU) is capable of reprogramming lineage dependence, which can be tuned to restore sensitivity to therapies that target the androgen receptor. We identify TARDBP and ZSCAN29 as DNA-binding proteins that directly engage the genomic locus of tRNA1Arg(UCU) to regulate its expression, a result that highlights the importance of non-canonical tRNA-specific gene regulation. Mechanistically, tRNA1Arg(UCU) controls a translational program centred on SWI/SNF chromatin remodellers, which is necessary to maintain lineage fidelity. In patients, tRNA1Arg(UCU) is downregulated in neuroendocrine prostate cancer and its loss is associated with accelerated metastasis and poor survival. These findings uncover a previously unrecognized tRNA-specific regulatory axis that links codon biology to lineage dependence and therapy resistance in prostate cancer.