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tRNA dosage regulates lineage dependency and resistance in prostate cancer
Nature
(2026) Cite this article
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.
Lineage plasticity is a cellular property that enables development and stress adaptation3,4. It is characterized by the ability of cells to differentiate into alternative identities that take on new epigenetic states, transcriptional programs and morphologies5,6,7. However, in the context of cancer, lineage plasticity is often co-opted as a response to therapies, pulling cancers away from their lineage-specific dependencies to drive drug resistance8. This is especially apparent in lineage-dependent cancers1, in which effective inhibition of the driver lineage factor9,10,11,12 can induce cellular reprogramming to promote cell survival. Like its tissue of origin13, prostate cancer requires the androgen receptor (AR) for growth14,15. However, genetic loss of TP53, PTEN or RB or treatment with second-generation AR pathway inhibitors (ARPIs) has been shown to drive lineage independence from the original AR-dependent lineage through neuroendocrine (NE) differentiation or alternative cell states16,17,18,19,20,21. Despite progress in defining the epigenetic and transcriptional mechanisms that underlie lineage dependencies and transitions in cancer1,2, the role of mRNA translation in controlling cell fate remains largely unexplored despite its substantial implications for therapy resistance and patient outcomes.
tRNAs are the crucial mediators of mRNA decoding that supply amino acids to growing polypeptide chains through the ribosome during protein synthesis22. tRNAs are organized into isoacceptor families—molecules that carry the same amino acid but differ in the anticodon—and are further subdivided into isodecoders that share anticodons but differ in their body sequences23 (Extended Data Fig. 1a). In mammals, approximately 300 unique isodecoders exist24. The advent of methods to quantify tRNA have revealed that tRNA dosage can vary significantly between different cell types and tissues25,26,27,28,29. This result suggests that tRNA abundance may be an important catalyst for distinct cellular functions in physiology30. Indeed, inherited mutations in various components of RNA polymerase III, the macromolecular complex responsible for tRNA synthesis, lead to tissue-specific diseases rather than a complete loss of cellular functions31. tRNA dysregulation has also been implicated in cancer, which highlights its broader impact on human disease32. Altered tRNA pools were first discovered in cancer in 2009 through microarray profiling of breast cancer33. Since then, growing evidence has shown that specific tRNAs can actively contribute to distinct cancer-promoting functions. Overexpression of the initiator tRNAiMet has been linked to increased proliferation in breast cancer and metastasis i