RESUMO
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome that elevates the risk of hepatocellular carcinoma (HCC). Although alteration of lipid metabolism has been increasingly recognized as a hallmark of cancer cells, the deregulated metabolic modulation of HCC cells in the NAFLD progression remains obscure. Here, we discovers an endoplasmic reticulum-residential protein, Nogo-B, as a highly expressed metabolic modulator in both murine and human NAFLD-associated HCCs, which accelerates high-fat, high-carbohydrate diet-induced metabolic dysfunction and tumorigenicity. Mechanistically, CD36-mediated oxLDL uptake triggers CEBPß expression to directly upregulate Nogo-B, which interacts with ATG5 to promote lipophagy leading to lysophosphatidic acid-enhanced YAP oncogenic activity. This CD36-Nogo-B-YAP pathway consequently reprograms oxLDL metabolism and induces carcinogenetic signaling for NAFLD-associated HCCs. Targeting the Nogo-B pathway may represent a therapeutic strategy for HCC arising from the metabolic syndrome.
Assuntos
Autofagia , Carcinoma Hepatocelular/metabolismo , Lipoproteínas LDL/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nogo/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Nogo/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Transdução de Sinais/genética , Transplante HeterólogoRESUMO
Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPß) which correlates with C/EBPß over-expression and poorer prognosis of patients. Demethylation of C/EBPß enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPß expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpß enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPß over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.
Assuntos
Carcinogênese/genética , Metilação de DNA , Neoplasias Hepáticas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Desmetilação , Epigênese Genética , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Transativadores , Fatores de Transcrição/metabolismo , Ativação Transcricional , Regulação para Cima , Proteínas Virais Reguladoras e AcessóriasRESUMO
Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.