When cells receive growth cues, they must carefully balance pro-proliferative signals with “brakes” that prevent uncontrolled division. In hormone-dependent cancers, this balance is strongly influenced by sex-hormone signaling, yet many RNA-based regulatory mechanisms downstream of these pathways remain underexplored.
Here, we report that a specific tRNA-derived small RNA, the 5′-tRNALysCUU half, promotes proliferation in androgen receptor–positive prostate cancer cells by facilitating cell cycle progression. Using global mRNA profiling following depletion of this tRNA half, we identified p21 (a key negative regulator of the cell cycle) as a central downstream target regulated at the post-transcriptional level.
Mechanistically, we found that YBX1, a 5′-tRNALysCUU half-binding protein, stabilizes p21 mRNA by binding to a specific sequence element in its 3′UTR. Importantly, binding assays demonstrated that the 5′-tRNALysCUU half can directly displace YBX1 from this site, leading to p21 mRNA destabilization and, consequently, accelerated cell cycle progression.
Collectively, our findings uncover a tRNA half-engaged mechanism that rewires mRNA stability control in hormone-dependent cancers, and suggest that tRNA halves may be part of broader regulatory networks operating through specific protein partners to tune gene expression programs that shape cell fate.
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References
- Kawamura, T, Shigematsu, M, Kirino, Y. A hormone-dependent tRNA half promotes cell cycle progression via destabilization of p21 mRNA. PLoS Biol. 2025;23 (6):e3003194. doi: 10.1371/journal.pbio.3003194. PubMed PMID:40471969 PubMed Central PMC12140204.