RESUMEN
mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis and is well known to be altered by oncogenes to promote cancer development. This distorted mRNA translation is accompanied by the vulnerability of cancer to inhibitors of key mRNA translation components. Novel studies also suggest that these alternations could be utilized for immunotherapy. Ribosome heterogeneity and alternative responses to nutrient shortages, which aid cancer growth and spread, are proposed to elicit aberrant protein production but may also result in previously unidentified therapeutic targets, such as the presentation of cancer-specific peptides at the surface of cancer cells (neoepitopes). This review will assess the driving forces in tRNA and ribosome function that underlie proteome diversification due to alterations in mRNA translation in cancer cells.
Asunto(s)
Neoplasias , Proteoma , Proteoma/genética , Proteoma/metabolismo , Biosíntesis de Proteínas , Ribosomas/genética , Ribosomas/metabolismo , Péptidos/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1-4. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides 'substitutants' to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.
Asunto(s)
Triptófano-ARNt Ligasa , Triptófano , Codón/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma , Neoplasias/inmunología , Fenilalanina , Linfocitos T , Triptófano/metabolismo , Triptófano Oxigenasa/genética , Triptófano Oxigenasa/metabolismo , Triptófano-ARNt Ligasa/genética , Triptófano-ARNt Ligasa/metabolismoRESUMEN
Accumulating evidence identifies non-genetic mechanisms substantially contributing to drug resistance in cancer patients. Preclinical and clinical data implicate the transcriptional co-activators YAP1 and its paralog TAZ in resistance to multiple targeted therapies, highlighting the strong need for therapeutic strategies overcoming YAP1/TAZ-mediated resistance across tumor entities. Here, we show particularly high YAP1/TAZ activity in MITFlow/AXLhigh melanomas characterized by resistance to MAPK pathway inhibition and broad receptor tyrosine kinase activity. To uncover genetic dependencies of melanoma cells with high YAP1/TAZ activity, we used a genome-wide CRISPR/Cas9 functional screen and identified SLC35B2, the 3'-phosphoadenosine-5'-phosphosulfate transporter of the Golgi apparatus, as an essential gene for YAP1/TAZ-driven drug resistance. SLC35B2 expression correlates with tumor progression, and its loss decreases heparan sulfate expression, reduces receptor tyrosine kinase activity, and sensitizes resistant melanoma cells to BRAF inhibition in vitro and in vivo. Thus, targeting heparan sulfation via SLC35B2 represents a novel approach for breaking receptor tyrosine kinase-mediated resistance to MAPK pathway inhibitors.
Asunto(s)
Melanoma , Línea Celular Tumoral , Resistencia a Antineoplásicos , Heparitina Sulfato/metabolismo , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
T helper 17 (Th17) cells have crucial functions in mucosal immunity and the pathogenesis of several chronic inflammatory diseases. The lineage-specific transcription factor, RORγt, encoded by the RORC gene modulates Th17 polarization and function, as well as thymocyte development. Here we define several regulatory elements at the human RORC locus in thymocytes and peripheral CD4+ T lymphocytes, with CRISPR/Cas9-guided deletion of these genomic segments supporting their role in RORγt expression. Mechanistically, T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements in activated CD4+ T cells. Meanwhile, NFAT proteins bind to these regulatory elements and activate RORγt transcription in cooperation with NF-kB. Our data thus demonstrate that NFAT specifically regulate RORγt expression by binding to the RORC locus and promoting its permissive conformation.
Asunto(s)
Regulación de la Expresión Génica , Factores de Transcripción NFATC/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Elementos Reguladores de la Transcripción/genética , Células Th17/metabolismo , Timocitos/metabolismo , Activación Transcripcional , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Sistemas CRISPR-Cas , Linaje de la Célula , Citometría de Flujo , Células HEK293 , Código de Histonas , Humanos , Células Jurkat , Células Th17/citología , Timocitos/citología , Factores de Transcripción p300-CBP/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.