tRNA dosage regulates lineage dependency and resistance in prostate cancer
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. A tRNA-specific regulatory pathway is associated with codon biology, lineage transitions and therapy resistance in prostate cancer.
Authors
- Andrew Caleb Hsieh (ORCID: https://orcid.org/0000-0002-0897-1050)
- Tao Pan (ORCID: https://orcid.org/0000-0003-1096-8405)
- Dmytro Rudoy (ORCID: https://orcid.org/0009-0000-5676-3355)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Samantha L. Schuster (ORCID: https://orcid.org/0000-0003-4051-5802)
- Mohammad Amin Bayat Tork (ORCID: https://orcid.org/0000-0002-2944-046X)
- Susan L. Ackerman (ORCID: https://orcid.org/0000-0002-6740-593X)
- Gavin Ha (ORCID: https://orcid.org/0000-0001-7578-7272)
- Arvind Rasi Subramaniam (ORCID: https://orcid.org/0000-0001-6145-4303)
- John K. Lee (ORCID: https://orcid.org/0000-0002-6570-2180)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Cynthia L. Wladyka
- Ilsa M. Coleman (ORCID: https://orcid.org/0000-0002-1483-7202)
- Sonali Arora (ORCID: https://orcid.org/0000-0002-6661-3024)
- Wen Zhang (ORCID: https://orcid.org/0000-0001-9400-9740)
- Yuzhuo Z. Wang (ORCID: https://orcid.org/0000-0002-9749-8591)
- Yeon Soo Kim (ORCID: https://orcid.org/0000-0002-7862-1662)
- Marek Sobczyk (ORCID: https://orcid.org/0009-0004-5698-5627)
- Christopher D. Katanski (ORCID: https://orcid.org/0000-0002-1707-081X)
- Morrissey Colm
- Mridu Kapur
- Dave Young
- Jin Yeong kim
- Michael C. Haffner
- Jennifer A. Waters
- Ava Tsou
- Amy Shiuan
Institutions
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- University of Washington (US)
- Vancouver General Hospital (CA)
- University of California San Diego (US)
- University of Chicago (US)
- Fred Hutch Cancer Center (US)
Publication Details
- Journal
- Nature
- Published
- 2026-10-07
- DOI
- https://doi.org/10.1038/s41586-026-11153-8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00