RESUMEN
Most of the cancer-associated mortality and morbidity can be attributed to metastasis. The role of epigenetic and epitranscriptomic alterations in cancer origin and progression has been extensively demonstrated during the last years. Both regulations share similar mechanisms driven by DNA or RNA modifiers, namely writers, readers, and erasers; enzymes responsible of respectively introducing, recognizing, or removing the epigenetic or epitranscriptomic modifications. Epigenetic regulation is achieved by DNA methylation, histone modifications, non-coding RNAs, chromatin accessibility, and enhancer reprogramming. In parallel, regulation at RNA level, named epitranscriptomic, is driven by a wide diversity of chemical modifications in mostly all RNA molecules. These two-layer regulatory mechanisms are finely controlled in normal tissue, and dysregulations are associated with every hallmark of human cancer. In this review, we provide an overview of the current state of knowledge regarding epigenetic and epitranscriptomic alterations governing tumor metastasis, and compare pathways regulated at DNA or RNA levels to shed light on a possible epi-crosstalk in cancer metastasis. A deeper understanding on these mechanisms could have important clinical implications for the prevention of advanced malignancies and the management of the disseminated diseases. Additionally, as these epi-alterations can potentially be reversed by small molecules or inhibitors against epi-modifiers, novel therapeutic alternatives could be envisioned.
Asunto(s)
Epigénesis Genética , Neoplasias , Humanos , Metilación de ADN , Neoplasias/patología , ARN/metabolismo , ADN/metabolismoRESUMEN
BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. RESULTS: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. CONCLUSION: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.
Asunto(s)
Neoplasias Hepáticas , Metiltransferasas , Humanos , 5-Metilcitosina , Islas de CpG , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo , Proteómica , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/genéticaRESUMEN
Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities.
Asunto(s)
Neoplasias/patología , Biosíntesis de Proteínas , Procesamiento Postranscripcional del ARN , ARN Ribosómico/metabolismo , ARN de Transferencia/metabolismo , Ribosomas/metabolismo , Animales , Humanos , Neoplasias/genética , ARN Ribosómico/química , ARN Ribosómico/genética , ARN de Transferencia/química , ARN de Transferencia/genética , Ribosomas/genéticaRESUMEN
Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Epigénesis Genética , Glioma/metabolismo , Metiltransferasas/metabolismo , Proteínas Musculares/metabolismo , Biosíntesis de Proteínas/fisiología , Ribosomas/metabolismo , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Metilación de ADN , Humanos , Metiltransferasas/genética , Ratones Desnudos , Proteínas Musculares/genética , Trasplante de Neoplasias , ARN Ribosómico 28SRESUMEN
Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Carcinogénesis/metabolismo , Glioma/metabolismo , Hidroxibutiratos/metabolismo , Células Madre Neoplásicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Anciano , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Carcinogénesis/patología , Muerte Celular/fisiología , Proliferación Celular/fisiología , Niño , Preescolar , Femenino , Glioma/patología , Glioma/cirugía , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Succionato-Semialdehído Deshidrogenasa/metabolismoRESUMEN
Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.
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Aldehído Deshidrogenasa/genética , Mutación/genética , Ornitina/genética , Ornitina/metabolismo , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Arginina/metabolismo , Femenino , Ácido Glutámico/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/metabolismo , Adulto JovenRESUMEN
SUMMARY: Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., p. 228 (8) .
Asunto(s)
Empalme Alternativo , Leucemia Linfocítica Crónica de Células B , Humanos , Empalme Alternativo/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Empalme del ARN , Metiltransferasas/genética , Metiltransferasas/metabolismo , Metiltransferasas/uso terapéutico , Factores de Empalme de ARN/genéticaRESUMEN
In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation.See related article by Deblois et al., p. 1312.
Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2 , Neoplasias , Metilación de ADN , Proteína Potenciadora del Homólogo Zeste 2/genética , Epigénesis Genética , Epigenómica , Histonas/genética , Histonas/metabolismo , HumanosRESUMEN
Mutations to the Krebs cycle enzyme fumarate hydratase in cancer cells leads to an accumulation of the oncometabolite fumarate. Sciacovelli et al. (2016) demonstrate an epigenetically dependent epithelial-to-mesenchymal transition mediated by modulation of the miR-200 cluster and TET demethylation in response to fumarate accumulation.
Asunto(s)
Transición Epitelial-Mesenquimal/genética , MicroARNs/genética , Fumarato Hidratasa/genética , Fumaratos , Humanos , MetilaciónRESUMEN
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.
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Neoplasias de las Glándulas Suprarrenales/genética , Neurofibromina 1/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Neoplasias de las Glándulas Suprarrenales/patología , Animales , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Noqueados , Mutación , Feocromocitoma/patologíaRESUMEN
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na(+)/H(+) exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
Asunto(s)
Benzo(a)pireno/toxicidad , Carcinógenos Ambientales/toxicidad , Reprogramación Celular/efectos de los fármacos , Hígado/citología , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Animales , Línea Celular , Supervivencia Celular , Ciclo del Ácido Cítrico/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Ácido Láctico/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , RatasRESUMEN
PURPOSE: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. EXPERIMENTAL DESIGN: A pulsed proton magnetic resonance spectroscopy ((1)H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb(-/-) or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. RESULTS: A succinate peak was observed at 2.44 ppm by (1)H-MRS in all Sdhb(-/-)-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, (1)H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. CONCLUSIONS: Detection of succinate by (1)H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors.
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Complejo II de Transporte de Electrones/genética , Proteínas de la Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Animales , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Paraganglioma/metabolismo , Paraganglioma/patología , Feocromocitoma/patología , Ácido Succínico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.
Asunto(s)
Complejo II de Transporte de Electrones/metabolismo , Proteínas de la Membrana/metabolismo , Tumores Neuroendocrinos/enzimología , Paraganglioma/enzimología , Ácido Pirúvico/metabolismo , Succinato Deshidrogenasa/metabolismo , Animales , Ácido Aspártico/metabolismo , Complejo II de Transporte de Electrones/genética , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Fosforilación Oxidativa , Paraganglioma/genética , Paraganglioma/metabolismo , Succinato Deshidrogenasa/genéticaRESUMEN
PURPOSE: Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). PATIENTS AND METHODS: Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. RESULTS: In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 µmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 µmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). CONCLUSION: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.
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Biomarcadores de Tumor/sangre , Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/diagnóstico , Mutación , Adulto , Anciano , Área Bajo la Curva , Femenino , Francia , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Neoplasia Residual/sangre , Proteínas Nucleares/sangre , Nucleofosmina , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Sensibilidad y Especificidad , Estereoisomerismo , Proteínas WT1/sangreRESUMEN
Paragangliomas are neuroendocrine tumors frequently associated with mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes. Methylome analysis of a large paraganglioma cohort identified three stable clusters, associated with distinct clinical features and mutational status. SDHx-related tumors displayed a hypermethylator phenotype, associated with downregulation of key genes involved in neuroendocrine differentiation. Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases and established a migratory phenotype reversed by decitabine treatment. Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy. Finally, inactivating FH mutations were identified in the only hypermethylated tumor without SDHx mutations. These findings emphasize the interplay between the Krebs cycle, epigenomic changes, and cancer.