Altered tRNA Isoacceptor Abundance Regulates Breast Cancer Metastasis

Once considered simple adapter molecules, tRNAs have become increasingly implicated in disease progression. Differential expression of tRNA isoacceptors, defined as tRNAs that decode synonymous codons of a given amino acid, has been observed in proliferative cells, but it remains unknown if altered transcriptional regulation of specific tRNAs affects cancer progression In this study, Earnest-Noble and colleagues examined the impact of tRNA expression on breast cancer progression using tRNA profiling and showed differential abundance of isoleucyl tRNA isoacceptors in highly metastatic versus poorly metastatic breast cancer cells, with highly metastatic cells displaying increased tRNA^Ile_UAU and decreased tRNA^Ile_GAU expression. Samples from patients with stage III breast cancer similarly had higher ratios of tRNA^Ile_UAU/tRNA^Ile_GAU expression compared with those with stage I–II breast cancer, suggesting that these alterations occur over the course of disease progression. Moreover, overexpression of tRNA^Ile_UAU or knockout of tRNA^Ile_GAU in poorly metastatic breast cancer cells led to increased lung metastatic colonization, while knockout of tRNA^Ile_UAU or overexpression of tRNA^Ile_GAU decreased lung metastases formed by highly metastatic cells. Genome-wide comparison of codons recognized by these tRNA isoacceptors showed that AUA codons, cognate to tRNA^Ile_UAU, were enriched in mitosis-related genes, while AUC codons, cognate to tRNA^Ile_GAU, were depleted in this gene set. The translational efficiency and protein levels of the mitotic genes SMNDC1, LSM6, and PYCARD were indeed upregulated in cells overexpressing tRNA^Ile_UAU and depleted of tRNA^Ile_GAU, and suppression of these mitotic genes reduced proliferation and metastatic colonization. Synonymous mutation of AUA to AUC codons in SMNDC1 did not lead to increased protein expression in the dual tRNA modulated cells, indicating that the AUA codon was responsible for enhanced translation. Accordingly, increased polysome occupancy and decreased ribosomal dwell time were observed in transcripts enriched with AUA codons compared with AUC in these cells, and tRNA^Ile_UAU demonstrated greater ribosomal association than tRNA^Ile_GAU, leading to higher translational efficiency. In summary, this study indicates that the altered expression of two isoleucyl isoacceptor tRNAs promotes metastasis by regulating mitotic gene expression during breast cancer progression.

Earnest-Noble LB, Hsu D, Chen S, Asgharian H, Nandan M, Passarelli MC, et al. Two isoleucyl tRNAs that decode synonymous codons divergently regulate breast cancer metastatic growth by controlling translation of proliferation-regulating genes. Nat Cancer 2022;3:1484–97.

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