GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301566/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301566GEOGSEfalsetRNA dosage regulates lineage plasticity and therapy resistance in prostate cancer through codon bias [Polysome-seq]Lineage plasticity underlies therapeutic resistance in cancer, yet the translational mechanisms enabling this phenotypic flexibility remain largely unknown. 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. These findings uncover a previously unrecognized tRNA-specific regulatory axis that links codon biology to lineage dependence and therapy resistance in prostate cancer.2026/08/26GSE301566GSM9085425GSM9085403GSM9085404GSM9085426GSM9085401GSM9085424GSM9085402GSM9085407GSM9085429GSM9085427GSM9085405GSM9085428GSM9085406GSM9085391GSM9085392GSM9085390GSM9085395GSM9085396GSM9085393GSM9085394GSM9085399GSM9085432GSM9085433GSM9085430GSM9085397GSM9085431GSM9085398GSM9085436GSM9085437GSM9085434GSM9085435GSM9085438GSM9085439GSM9085384GSM9085385GSM9085388GSM9085400GSM9085389GSM9085386GSM908538724676301566Homo sapiens