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1.
Cell ; 150(6): 1135-46, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22980977

RESUMO

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.


Assuntos
Citosina/análogos & derivados , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Nevo/genética , 5-Metilcitosina/análogos & derivados , Citosina/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases , Estudo de Associação Genômica Ampla , Humanos , Isocitrato Desidrogenase/genética , Melanócitos/metabolismo , Melanoma/patologia , Nevo/patologia , Proteínas Proto-Oncogênicas/genética
2.
Nature ; 559(7715): 637-641, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30022161

RESUMO

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.


Assuntos
Adenilato Quinase/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Animais , DNA/química , DNA/metabolismo , Metilação de DNA , Diabetes Mellitus/genética , Dioxigenases , Estabilidade Enzimática , Epigênese Genética , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fosforilação , Fosfosserina/metabolismo , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Mol Carcinog ; 54(11): 1503-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25154389

RESUMO

The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis.


Assuntos
Ácidos Aristolóquicos/toxicidade , Carcinógenos/toxicidade , Citosina/análogos & derivados , Fígado/metabolismo , Alcaloides de Pirrolizidina/toxicidade , 5-Metilcitosina/análogos & derivados , Animais , Carcinogênese/efeitos dos fármacos , Citosina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética/efeitos dos fármacos , Mutação/efeitos dos fármacos , Neoplasias/induzido quimicamente , Neoplasias/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos
4.
Int J Mol Sci ; 16(9): 21791-801, 2015 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-26370990

RESUMO

Non-bullous congenital ichthyosiform erythroderma (NBCIE) is a hereditary disorder of keratinization caused by pathogenic variants in genes encoding enzymes important to lipid processing and terminal keratinocyte differentiation. Impaired function of these enzymes can cause pathologic epidermal scaling, significantly reduced skin barrier function. In this study, we have performed a focused, genetic analysis of a probrand affected by NBCIE and extended this to his consanguineous parents. Targeted capture and next-generation sequencing was performed on NBCIE associated genes in the proband and his unaffected consanguineous parents. We identified a homozygous nonsense variant c.814C>T (p.Arg272*) in ALOXE3 (NM_001165960.1) in the proband and discovered that his parents are both heterozygous carriers of the variant. The clinical manifestations of the proband's skin were consistent with NBCIE, and detailed histopathological assessment revealed epidermal bulla formation and Majocchi's granuloma. Infection with Trichophyton rubrum was confirmed by culture. The patient responded to oral terbinafine antifungal treatment. Decreased skin barrier function, such as that caused by hereditary disorders of keratinization, can increase the risk of severe cutaneous fungal infections and the formation of Majocchi's granuloma and associated alopecia. Patients with NBCIE should be alerted to the possible predisposition for developing dermatophytoses and warrant close clinical follow-up.


Assuntos
Códon sem Sentido , Homozigoto , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Lipoxigenase/genética , Biópsia , Criança , Consanguinidade , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ictiose Lamelar/complicações , Ictiose Lamelar/tratamento farmacológico , Masculino , Naftalenos/administração & dosagem , Naftalenos/uso terapêutico , Linhagem , Fenótipo , Pele/metabolismo , Pele/patologia , Terbinafina , Resultado do Tratamento
5.
Mod Pathol ; 27(7): 936-44, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24390216

RESUMO

DNA methylation is the most well-studied epigenetic modification in cancer biology. 5-hydroxymethylcytosine is an epigenetic mark that can be converted from 5-methylcytosine by the ten-eleven translocation gene family. We recently reported the loss of 5-hydroxymethylcytosine in melanoma compared with benign nevi and suggested that loss of this epigenetic marker is correlated with tumor virulence based on its association with a worse prognosis. In this study, we further characterize the immunoreactivity patterns of 5-hydroxymethylcytosine in the full spectrum of melanocytic lesions to further validate the potential practical application of this epigenetic marker. One hundred and seventy-five cases were evaluated: 18 benign nevi, 20 dysplastic nevi (10 low-grade and 10 high-grade lesions), 10 atypical Spitz nevi, 20 borderline tumors, 5 melanomas arising within nevi, and 102 primary melanomas. Progressive loss of 5-hydroxymethylcytosine from benign dermal nevi to high-grade dysplastic nevi to borderline melanocytic neoplasms to melanoma was observed. In addition, an analysis of the relationship of nuclear diameter with 5-hydroxymethylcytosine staining intensity within lesional cells revealed a significant correlation between larger nuclear diameter and decreased levels of 5-hydroxymethylcytosine. Furthermore, borderline lesions uniquely exhibited a diverse spectrum of staining of each individual case. This study further substantiates the association of 5-hydroxymethylcytosine loss with dysplastic cytomorphologic features and tumor progression and supports the classification of borderline lesions as a biologically distinct category of melanocytic lesions.


Assuntos
Citosina/análogos & derivados , Melanoma/genética , Nevo/genética , Lesões Pré-Cancerosas/genética , Neoplasias Cutâneas/genética , 5-Metilcitosina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Cutâneas/patologia , Adulto Jovem
6.
Mod Pathol ; 27(6): 788-99, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24434898

RESUMO

This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donor-versus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated.


Assuntos
Transplante de Face/efeitos adversos , Rejeição de Enxerto/imunologia , Reação Enxerto-Hospedeiro/imunologia , Linfócitos T/imunologia , Adulto , Aloenxertos , Biomarcadores/análise , Imunofluorescência , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Doadores de Tecidos
7.
Int J Oncol ; 54(5): 1534-1544, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816486

RESUMO

Cell division cycle 20 (CDC20) is a regulatory molecule and serves critical roles at multiple points of the cell cycle. Recent evidence indicates that CDC20 may serve an oncogenic role in a number of human cancer types. However, the role of CDC20 in primary cutaneous squamous cell carcinoma (cSCC) has not been studied, to the best of our knowledge. The aim of the present study was to investigate whether and how CDC20 is involved in the tumorigenesis of cSCC. The results revealed that CDC20 expression was significantly increased in cSCC tissues and cell lines, and its expression was associated with pathological differentiation. Downregulation of CDC20 inhibited cell proliferation, induced cell cycle arrest, promoted apoptosis and reduced migratory ability through inhibition of the Wnt/ß­catenin signaling pathway. Furthermore, all­trans­retinoic acid treatment significantly downregulated CDC20 expression in cSCC. The present results revealed that CDC20 may serve a crucial role in human cSCC, and suggested that CDC20 may be a novel biomarker for the prevention, diagnosis and treatment of cSCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Neoplasias Cutâneas/metabolismo , Regulação para Cima , Via de Sinalização Wnt , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto Jovem
8.
An Bras Dermatol ; 93(2): 216-221, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29723350

RESUMO

BACKGROUND: Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. OBJECTIVE: The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. METHODS: This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. RESULTS: One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously. Of these patients, five presented with generalized papules or nodules, and five with localized masses. The biopsy of skin lesions showed a large number of tumor cells within the dermis and subcutaneous fat layer. Immunohistochemical analysis showed strong reactivity to myeloperoxidase (MPO), CD15, CD43 and CD45 (LCA) in most cases. NPM1 (nucleophosmin I) and FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication) mutations were identified in one case. Five patients with acute myelogenous leukemia and one patient with chronic myelomonocytic leukemia died within two months to one year after the onset of skin lesions. STUDY LIMITATIONS: This was a retrospective and small sample study. CONCLUSIONS: In patients with myelogenous leukemia, skin infiltration usually occurs after, but occasionally before, the appearance of hemogram and myelogram abnormalities, and the presence of skin infiltration is often associated with a poor prognosis and short survival time. myeloid leukemia cutis often presents as generalized or localized nodules or masses with characteristic pathological and histochemical findings.


Assuntos
Leucemia Mieloide/patologia , Infiltração Leucêmica/patologia , Pele/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo
9.
J Invest Dermatol ; 138(11): 2388-2397, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29803640

RESUMO

DNA hydroxymethylation at the 5 position of cytosine (5-hmC) is a product of the TET family of DNA hydroxylases. Accumulating evidence shows that loss of 5-hmC is critical for various biological and pathological processes. However, its level in cutaneous T-cell lymphoma (CTCL) remains largely unknown. Here, we report that the loss of 5-hmC is an epigenetic hallmark of CTCL, with diagnostic and prognostic implications. Immunohistochemistry staining on 90 mycosis fungoides (MF) samples showed a significant decrease of 5-hmC staining in CD4+ T cells in patch and tumor stages, especially in MF with large cell transformation, compared with benign inflammatory dermatoses. The 5-hmC staining level decreased with disease progression and showed remarkable loss in the large cells of large cell transformed MF samples, regardless of the CD30 positivity. Furthermore, 5-hmC decrease was correlated to poor overall survival in our patient cohort. Pharmacological augments of global 5-hmC with l-ascorbic acid in CTCL cell lines led to remarkable 5-hmC accumulation and promoted apoptosis in CTCL cell lines, as well as in patient-derived CTCL cells. In conclusion, 5-hmC is an epigenetic mark of predictive value in MF prognosis. Restoration of 5-hmC levels in MF may serve as a therapeutic regimen in CTCL.


Assuntos
5-Metilcitosina/análogos & derivados , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Queratinócitos/fisiologia , Linfoma Cutâneo de Células T/diagnóstico , Micose Fungoide/diagnóstico , Neoplasias Cutâneas/diagnóstico , 5-Metilcitosina/metabolismo , Apoptose , Carcinogênese , Linhagem Celular Tumoral , Progressão da Doença , Epigênese Genética , Feminino , Humanos , Linfoma Cutâneo de Células T/mortalidade , Masculino , Estadiamento de Neoplasias , Prognóstico , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida
10.
JAMA Dermatol ; 150(12): 1336-40, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25188413

RESUMO

IMPORTANCE Port-wine stains (PWSs) are common congenital cutaneous capillary malformations. A somatic GNAQ mutation was recently identified in patients with sporadic PWSs and Sturge-Weber syndrome. However, subsequent studies to confirm or extend this observation are lacking.OBSERVATIONS We report a long-standing, unilateral facial PWS of a man in his early 70s confirmed by histopathological analysis. Staged surgical excision of the vascular malformation was performed, and genomic DNA was extracted from the vascular malformation specimen and normal skin. Targeted next-generation sequencing of the coding sequence of 275 known cancer genes including GNAQ was performed in both specimens. A single-nucleotide variant(c.548G>A, p.Arg183Gln) in GNAQ was identified in the PWS-affected tissue but not in the normal skin sample. In addition, this sequencing approach uncovered several additional novel somatic mutations in the genes SMARCA4, EPHA3, MYB, PDGFR-ß, and PIK3CA.CONCLUSIONS AND RELEVANCE Our findings confirm the presence of somatic mutations inGNAQ in the affected skin of a patient with congenital PWS, as well as alterations in several other novel genes of possible importance in the pathogenesis of PWS that may also offer substantial therapeutic targets.


Assuntos
Dermatoses Faciais/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Mancha Vinho do Porto/genética , Idoso , Classe I de Fosfatidilinositol 3-Quinases , DNA Helicases/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Genes myb/genética , Humanos , Masculino , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único , Mancha Vinho do Porto/cirurgia , Receptores Proteína Tirosina Quinases/genética , Receptor EphA3 , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Transcrição/genética
11.
An. bras. dermatol ; An. bras. dermatol;93(2): 216-221, Mar.-Apr. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-887171

RESUMO

Abstract: Background: Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. Objective: The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. Methods: This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. Results: One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously. Of these patients, five presented with generalized papules or nodules, and five with localized masses. The biopsy of skin lesions showed a large number of tumor cells within the dermis and subcutaneous fat layer. Immunohistochemical analysis showed strong reactivity to myeloperoxidase (MPO), CD15, CD43 and CD45 (LCA) in most cases. NPM1 (nucleophosmin I) and FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication) mutations were identified in one case. Five patients with acute myelogenous leukemia and one patient with chronic myelomonocytic leukemia died within two months to one year after the onset of skin lesions. Study limitations: This was a retrospective and small sample study. Conclusions: In patients with myelogenous leukemia, skin infiltration usually occurs after, but occasionally before, the appearance of hemogram and myelogram abnormalities, and the presence of skin infiltration is often associated with a poor prognosis and short survival time. myeloid leukemia cutis often presents as generalized or localized nodules or masses with characteristic pathological and histochemical findings.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Pele/patologia , Leucemia Mieloide/patologia , Infiltração Leucêmica/patologia , Prognóstico , Fatores de Tempo , Biópsia , Imuno-Histoquímica , Fatores Sexuais , Estudos Retrospectivos , Fatores Etários
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