Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics

Passarelli, Maria C.; Pinzaru, Alexandra M.; Asgharian, Hosseinali; Liberti, Maria V.; Heissel, Søren; Molina, Henrik; Goodarzi, Hani; Tavazoie, Sohail F.

doi:10.1038/s41556-022-00856-5

Cited by 40 publications

(34 citation statements)

References 59 publications

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“…Repression of LARS lead to impaired leucine codon-dependent translation of growth suppressive genes, including gammaglutamyltransferase 5 (GGT5) and epithelial membrane protein 3 (EMP3). which in turn enhances breast tumor formation and growth [32]. These results indicated that the function of LARS is complex, as it appears to have different functions in different tumors.…”

Section: Discussionmentioning

confidence: 89%

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

et al. 2022

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Background Osteosarcoma is one of the most malignant tumors, and it occurs mostly in children and adolescents. Currently, surgery and chemotherapy are the main treatments. The recurrence rate is high and the prognosis is often poor. Finding an effective target gene therapy for osteosarcoma may effectively improve its prognosis. Method In this study, genes essential for the survival of osteosarcoma cells were identified by genome-wide screening of CRISPR-Cas9 based on the DepMap database. The expression of these essential genes in osteosarcoma patients’ tissues and normal tissues was identified in the GSE19276 database. Functional pathway enrichment analysis, protein interaction network construction, and LASSO were performed to construct a prognostic risk model based on these essential genes. CCK8 assay was used to detect the effect of essential gene-LARS (Leucyl-TRNA Synthetase 1) on the proliferation of osteosarcoma. Results In this study, 785 genes critical for osteosarcoma cell proliferation were identified from the DepMap. Among these 785 essential genes, 59 DEGs were identified in osteosarcoma tissues. In the functional enrichment analysis, these 59 essential genes were mainly enriched in cell cycle-related signaling pathways. Furthermore, we established a risk score module, including LARS and DNAJC17, screened from these 59 genes, and this module could divide osteosarcoma patients into the low-risk and high-risk groups. In addition, knockdown of LARS expression inhibited the proliferative ability of osteosarcoma cells. A significant correlation was found between LARS expression and Monocytic lineage, T cells, and Fibroblasts. Conclusion In conclusion, LARS was identified as an essential gene for survival in osteosarcoma based on the DepMap database. Knockdown of LARS expression significantly inhibited the proliferation of osteosarcoma cells, suggesting that it is involved in the formation and development of osteosarcoma. The results are useful as a foundation for further studies to elucidate a potential osteosarcoma diagnostic index and therapeutic targets.

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Section: Discussionmentioning

confidence: 89%

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

et al. 2022

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“…We hypothesized that one mechanism that could contribute to arginine tRNA repression may be reduced tRNA aminoacylation in the setting of arginine limitation. Reduced aminoacylation of certain tRNAs has been shown to destabilize tRNAs ( 21 ). To test this, we inhibited aminoacylation in CRC cells by depleting the arginyl-tRNA synthetase (RARS) and quantified tRNA levels.…”

Section: Resultsmentioning

confidence: 99%

Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells

et al. 2023

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Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation—a feature of tumor microenvironments—is sufficient to induce arginine codon–switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon–containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons—reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

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“…CD109, a known biomarker of brain tumors, was also elevated more in the PIK3CA E545K EVs than in their cells of origin [71]. Interestingly, leucine‐tRNA ligase (LARS), a tumor suppressor in breast cancers, was decreased in the EVs compared to their cells of origin [72]. Similarly, integrin beta‐4 (ITGB4), laminin subunit beta‐2 (LAMB2), and protein S100‐A14 (S100A14) were elevated in PIK3CA H1047R EVs more than in their cells of origin.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, leucine-tRNA ligase (LARS), a tumor suppressor in breast cancers, was decreased in the EVs compared to their cells of origin [72].…”

Section: Comparison With Cellular Proteomementioning

confidence: 99%

Proteomic alterations in extracellular vesicles induced by oncogenic PIK3CA mutations

et al. 2022

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PIK3CA is one of the most frequently mutated genes in human cancers, with the two most prevalent activating mutations being E545K and H1047R. Although the altered intracellular signaling pathways in these cells have been described, the effect of these mutations on their extracellular vesicles (EVs) has not yet been reported. To study altered cellular physiology and intercellular communication through proteomic analysis of EVs, MCF10A cells and their isogenic mutant versions (PIK3CA E545K and H1047R) were cultured and their EVs enriched by differential ultracentrifugation. Proteins were extracted, digested with trypsin and the peptides labeled with tandem mass tag (TMT) reagents and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Four thousand six hundred and fifty-five peptides were identified from 579 proteins of which 522 proteins have been previously described in EVs. Relative quantitation revealed altered levels of EV proteins including several cell adhesion molecules. Mesothelin, E-cadherin, and epithelial cell adhesion molecule were elevated in both mutant cell-derived EVs. Markers of tumor invasion and progression like galectin-3 and transforming growth factor beta induced protein were increased in both mutants. Overall, activating mutations in PIK3CA result in altered EV composition with characteristic changes associated with these hotspot mutations.

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Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics

Cited by 40 publications

References 59 publications

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells

Proteomic alterations in extracellular vesicles induced by oncogenic PIK3CA mutations

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