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Targeting tRNA-Arg-TCT-4-1 suppresses cancer cell growth and tumorigenesis

Esteban A Orellana1,2,3, Isobel E Bowles1,2, Xin Yang3,4

  • 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth. Hanover, NH, 03755 USA.

Biorxiv : the Preprint Server for Biology
|February 27, 2026
PubMed

Insights

This study reveals that elevated tRNA-Arg-TCT-4-1 levels correlate with poor cancer prognosis. Inhibiting this specific transfer RNA (tRNA) with an antisense oligonucleotide (ASO) suppressed tumor growth and improved survival in preclinical models.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Transfer RNAs (tRNAs) are crucial for protein synthesis and can influence cancer progression.
  • The specific role of endogenous tRNA-Arg-TCT isodecoders in cancer remains largely unexplored.
  • tRNA-Arg-TCT-4-1 is a potential oncogenic driver whose necessity in cancer has not been established.

Purpose of the Study:

  • To investigate the role of the tRNA-Arg-TCT-4-1 isodecoder in human cancers.
  • To determine if inhibiting tRNA-Arg-TCT-4-1 can suppress cancer cell growth and tumor progression.
  • To explore the therapeutic potential of targeting tRNA-Arg-TCT-4-1 in cancer treatment.

Main Methods:

  • Analysis of tRNA-Arg-TCT-4-1 expression levels in patient data across various cancer types.
  • Utilizing antisense RNA strategies to specifically inhibit tRNA-Arg-TCT-4-1 in glioblastoma (GBM) and liposarcoma (LPS) cell lines.
  • Investigating the impact of tRNA-Arg-TCT-4-1 inhibition on mRNA translation and proteome remodeling.
  • Conducting intratumoral delivery of an antisense oligonucleotide (ASO) targeting tRNA-Arg-TCT-4-1 in mouse xenograft models.

Main Results:

  • Elevated tRNA-Arg-TCT-4-1 levels are associated with poor patient prognosis in multiple cancers.
  • Specific inhibition of tRNA-Arg-TCT-4-1 suppressed the growth of GBM and LPS cancer cells.
  • tRNA-Arg-TCT-4-1 inhibition induced codon-biased translation changes, reducing expression of growth-promoting genes.
  • Intratumoral ASO delivery targeting tRNA-Arg-TCT-4-1 suppressed tumor growth and extended survival in preclinical models.

Conclusions:

  • tRNA-Arg-TCT-4-1 is a critical driver in certain cancers and a potential therapeutic target.
  • Antisense oligonucleotide (ASO)-mediated inhibition of tRNA-Arg-TCT-4-1 shows promise for cancer therapy.
  • Targeting tRNA dysregulation represents a novel strategy for cancer treatment.
Keywords:
antisensecancerinhibitionisodecodermRNA translationtRNAtRNA-Arg-TCT-4-1

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