Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
07 Jun 2024
07 Jun 2024
Historique:
received:
06
07
2023
accepted:
12
05
2024
medline:
8
6
2024
pubmed:
8
6
2024
entrez:
7
6
2024
Statut:
aheadofprint
Résumé
Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
Identifiants
pubmed: 38849541
doi: 10.1038/s41556-024-01439-2
pii: 10.1038/s41556-024-01439-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Worldwide Cancer Research
ID : 23-0288
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
Références
Davis, L. E., Shalin, S. C. & Tackett, A. J. Current state of melanoma diagnosis and treatment. Cancer Biol. Ther. 20, 1366 (2019).
pubmed: 31366280
pmcid: 6804807
doi: 10.1080/15384047.2019.1640032
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
pubmed: 12068308
doi: 10.1038/nature00766
Tanda, E. T. et al. Current state of target treatment in BRAF mutated melanoma. Front. Mol. Biosci. 7, 154 (2020).
pubmed: 32760738
pmcid: 7371970
doi: 10.3389/fmolb.2020.00154
Eroglu, Z. & Ribas, A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther. Adv. Med. Oncol. 8, 48 (2016).
pubmed: 26753005
pmcid: 4699264
doi: 10.1177/1758834015616934
Salgia, R. & Kulkarni, P. The genetic/non-genetic duality of drug ‘resistance’ in cancer. Trends Cancer 4, 110 (2018).
pubmed: 29458961
pmcid: 5822736
doi: 10.1016/j.trecan.2018.01.001
Rambow, F., Marine, J. C. & Goding, C. R. Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities. Genes Dev. 33, 1295–1318 (2019).
pubmed: 31575676
pmcid: 6771388
doi: 10.1101/gad.329771.119
Shen, S. et al. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nat. Commun. 10, 5713 (2019).
pubmed: 31844050
pmcid: 6915789
doi: 10.1038/s41467-019-13360-6
Boussemart, L. et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature https://doi.org/10.1038/nature13572 (2014).
doi: 10.1038/nature13572
pubmed: 25079330
Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature https://doi.org/10.1038/s41586-018-0243-7 (2018).
doi: 10.1038/s41586-018-0243-7
pubmed: 29925953
Passarelli, M. C. et al. Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics. Nat. Cell Biol. 24, 307–315 (2022).
pubmed: 35288656
pmcid: 8977047
doi: 10.1038/s41556-022-00856-5
Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416 (2016).
pubmed: 27259150
pmcid: 4915377
doi: 10.1016/j.cell.2016.05.046
Cui, H. et al. Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2. Nat. Cell Biol. 25, 592–603 (2023).
pubmed: 37059883
doi: 10.1038/s41556-023-01118-8
Wu, J. et al. Glutamyl-prolyl-tRNA synthetase regulates proline-rich pro-fibrotic protein synthesis during cardiac fibrosis. Circ. Res. 127, 827–846 (2020).
pubmed: 32611237
pmcid: 7484271
doi: 10.1161/CIRCRESAHA.119.315999
Yao, P. & Fox, P. L. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol. Med. https://doi.org/10.1002/emmm.201100626 (2013).
doi: 10.1002/emmm.201100626
pubmed: 23857777
pmcid: 3799489
Wei, N., Zhang, Q. & Yang, X. L. Neurodegenerative Charcot–Marie–Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases. J. Biol. Chem. https://doi.org/10.1074/jbc.REV118.002955 (2019).
doi: 10.1074/jbc.REV118.002955
pubmed: 31914406
pmcid: 7008366
Friedman, J. et al. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nat. Commun. https://doi.org/10.1038/s41467-018-07067-3 (2019).
doi: 10.1038/s41467-018-07067-3
pubmed: 31548585
pmcid: 6757065
Jeong, S. J. et al. Inhibition of muc1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration. Exp. Mol. Med. https://doi.org/10.1038/emm.2017.231 (2018).
Song, D. G. et al. Glutamyl-prolyl-tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms. FASEB J. https://doi.org/10.1096/fj.201801344RR (2019).
doi: 10.1096/fj.201801344RR
pubmed: 31914695
pmcid: 6902681
Falletta, P., Goding, C. R. & Vivas-García, Y. Connecting metabolic rewiring with phenotype switching in melanoma. Front. Cell Dev. Biol. 10, 930250 (2022).
pubmed: 35912100
pmcid: 9334657
doi: 10.3389/fcell.2022.930250
Leucci, E., Close, P. & Marine, J. C. Translation rewiring at the heart of phenotype switching in melanoma. Pigment Cell Melanoma Res. 30, 282–283 (2017).
pubmed: 28222245
doi: 10.1111/pcmr.12583
Liu, W. et al. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nat. Commun. 12, 5103 (2021).
pubmed: 34429409
pmcid: 8385107
doi: 10.1038/s41467-021-25354-4
Aloia, A. et al. A fatty acid oxidation-dependent metabolic shift regulates the adaptation of BRAF-mutated melanoma to MAPK inhibitors. Clin. Cancer Res. 25, 6852–6867 (2019).
pubmed: 31375515
pmcid: 6906212
doi: 10.1158/1078-0432.CCR-19-0253
Tang, Y., Durand, S., Dalle, S. & Caramel, J. EMT-Inducing transcription factors, drivers of melanoma phenotype switching, and resistance to treatment. Cancers 12, 1–17 (2020).
doi: 10.3390/cancers12082154
Rapino, F. et al. Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate. Nat. Commun. https://doi.org/10.1038/s41467-021-22254-5 (2021).
Pavon-Eternod, M. et al. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. https://doi.org/10.1093/nar/gkp787 (2009).
doi: 10.1093/nar/gkp787
pubmed: 19783824
pmcid: 2790902
Tang, Z. et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45, W98–W102 (2017).
pubmed: 28407145
pmcid: 5570223
doi: 10.1093/nar/gkx247
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell https://doi.org/10.1016/j.cell.2018.06.025 (2018).
doi: 10.1016/j.cell.2018.06.025
pubmed: 30017245
Loayza-Puch, F. et al. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature 530, 490–494 (2016).
pubmed: 26878238
doi: 10.1038/nature16982
Aloia, A. et al. PO-241 targeting fatty acid oxidation and glycolysis to overcome drug resistance to MAPK inhibitors. ESMO Open 3, A114 (2018).
doi: 10.1136/esmoopen-2018-EACR25.274
Shen, S. et al. Melanoma persister cells are tolerant to BRAF/MEK inhibitors via ACOX1-mediated fatty acid oxidation. Cell Rep. 33, 108421 (2020).
pubmed: 33238129
doi: 10.1016/j.celrep.2020.108421
Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018).
pubmed: 29925953
doi: 10.1038/s41586-018-0243-7
Thandapani, P. et al. Valine tRNA levels and availability regulate complex I assembly in leukaemia. Nature 601, 428–433 (2021).
pubmed: 34937946
pmcid: 9116157
doi: 10.1038/s41586-021-04244-1
Lipman, R. S. A. & Hou, Y. M. Aminoacylation of tRNA in the evolution of an aminoacyl-tRNA synthetase. Proc. Natl Acad. Sci. USA 95, 13495–13500 (1998).
pubmed: 9811828
pmcid: 24847
doi: 10.1073/pnas.95.23.13495
Schmidt, E. & Schimmel, P. Mutational isolation of a sieve for editing in a transfer RNA synthetase. Science 264, 265–267 (1994).
pubmed: 8146659
doi: 10.1126/science.8146659
Ou, X., Cao, J., Cheng, A., Peppelenbosch, M. P. & Pan, Q. Errors in translational decoding: tRNA wobbling or misincorporation? PLoS Genet. 15, e1008017 (2019).
pubmed: 30921315
pmcid: 6438450
doi: 10.1371/journal.pgen.1008017
Schimmel, P. Mistranslation and its control by tRNA synthetases. Philos. Trans. R. Soc. Lond. B 366, 2965–2971 (2011).
doi: 10.1098/rstb.2011.0158
Buck, C. A. & Nass, M. M. K. Studies on mitochondrial tRNA from animal cells. I. A comparison of mitochondrial and cytoplasmic trna and aminoacyl-tRNA synthetases. J. Mol. Biol. 41, 67–82 (1969).
pubmed: 4308495
doi: 10.1016/0022-2836(69)90126-0
Lynch, D. C. & Attardi, G. Amino acid specificity of the transfer RNA species coded for by HeLa cell mitochondrial DNA. J. Mol. Biol. 102, 125–141 (1976).
pubmed: 775098
doi: 10.1016/0022-2836(76)90077-2
Castresana, J., Feldmaier-Fuchs, G. & Pääbo, S. Codon reassignment and amino acid composition in hemichordate mitochondria. Proc. Natl Acad. Sci. USA 95, 3703–3707 (1998).
pubmed: 9520430
pmcid: 19900
doi: 10.1073/pnas.95.7.3703
Pataskar, A. et al. Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. Nature 603, 721–727 (2022).
pubmed: 35264796
pmcid: 8942854
doi: 10.1038/s41586-022-04499-2
Irvine, M. et al. Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. Oncogenesis 7, 72 (2018).
Putney, S. D. & Schimmel, P. An aminoacyl tRNA synthetase binds to a specific DNA sequence and regulates its gene transcription. Nature 291, 632–635 (1981).
pubmed: 6264314
doi: 10.1038/291632a0
Vitreschak, A. G., Mironov, A. A., Lyubetsky, V. A. & Gelfand, M. S. Comparative genomic analysis of T-box regulatory systems in bacteria. RNA 14, 717–735 (2008).
pubmed: 18359782
pmcid: 2271356
doi: 10.1261/rna.819308
Ma, Y. et al. Fatty acid oxidation: an emerging facet of metabolic transformation in cancer. Cancer Lett. 435, 92–100 (2018).
pubmed: 30102953
pmcid: 6240910
doi: 10.1016/j.canlet.2018.08.006
Wang, J., Xiang, H., Lu, Y., Wu, T. & Ji, G. The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression. Am. J. Cancer Res. 11, 2477 (2021).
pubmed: 34249411
pmcid: 8263643
Han, S. et al. CPT1A/2-mediated FAO enhancement—a metabolic target in radioresistant breast cancer. Front. Oncol. 9, 1201 (2019).
pubmed: 31803610
pmcid: 6873486
doi: 10.3389/fonc.2019.01201
Lukarska, M. & Palencia, A. Aminoacyl-tRNA synthetases as drug targets. Enzymes 48, 321–350 (2020).
pubmed: 33837708
doi: 10.1016/bs.enz.2020.07.001
Park, M. C. et al. Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis. Proc. Natl Acad. Sci. USA 109, E640–E647 (2012).
pubmed: 22345558
pmcid: 3306665
doi: 10.1073/pnas.1200194109
Zhou, Z., Sun, B., Nie, A., Yu, D. & Bian, M. Roles of aminoacyl-tRNA synthetases in cancer. Front. Cell Dev. Biol. 8, 599765 (2020).
pubmed: 33330488
pmcid: 7729087
doi: 10.3389/fcell.2020.599765
Kim, E. Y., Jung, J. Y., Kim, A., Kim, K. & Chang, Y. S. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer 17, 467 (2017).
pubmed: 28679377
pmcid: 5497355
doi: 10.1186/s12885-017-3452-9
Wellman, T. L. et al. Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer. BMC Cancer 14, 620 (2014).
pubmed: 25163878
pmcid: 4155084
doi: 10.1186/1471-2407-14-620
Ahn, Y. H., Oh, S. C., Zhou, S. & Kim, T. D. Tryptophanyl‐tRNA synthetase as a potential therapeutic target. Int. J. Mol. Sci. 22, 4523 (2021).
pubmed: 33926067
pmcid: 8123658
doi: 10.3390/ijms22094523
Liang, S. et al. Polysome-profiling in small tissue samples. Nucleic Acids Res. 46, E3 (2018).
pubmed: 29069469
doi: 10.1093/nar/gkx940
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
pubmed: 29203879
pmcid: 5715110
doi: 10.1038/s41598-017-17204-5
Hänzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
pubmed: 25605792
pmcid: 4402510
doi: 10.1093/nar/gkv007
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Heiman, M., Kulicke, R., Fenster, R. J., Greengard, P. & Heintz, N. Cell type-specific mRNA purification by translating ribosome affinity purification (TRAP). Nat. Protoc. 9, 1282–1291 (2014).
pubmed: 24810037
pmcid: 4102313
doi: 10.1038/nprot.2014.085