Hepatoblastomas exhibit marked<i>NNMT</i>downregulation driven by promoter DNA hypermethylation

  • Maria Prates Rivas
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Talita Ferreira Marques Aguiar
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Mariana Maschietto
    Research Center, Boldrini Children’s Hospital, Campinas, Brazil
  • Renan B Lemes
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Luiz Carlos Caires-Júnior
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Ernesto Goulart
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Kayque Alves Telles-Silva
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Estela Novak
    Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
  • Lilian Maria Cristofani
    Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
  • Vicente Odone
    Pediatric Cancer Institute (ITACI) at the Pediatric Department, São Paulo University Medical School, São Paulo, Brazil
  • Monica Cypriano
    Department of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, Brazil
  • Silvia Regina Caminada de Toledo
    Department of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of São Paulo, São Paulo, Brazil
  • Dirce Maria Carraro
    International Center for Research, A.C. Camargo Cancer Center, São Paulo, Brazil
  • Melissa Quintero Escobar
    Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, Brazil
  • Hana Lee
    Department of Surgery, Division of General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  • Michael Johnston
    Department of Surgery, Division of General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  • Cecilia Maria Lima da Costa
    Department of Pediatric Oncology, A.C. Camargo Cancer Center, São Paulo, Brazil
  • Isabela Werneck da Cunha
    Department of Pathology, Rede D’OR São Luiz, São Paulo, Brazil
  • Ljubica Tasic
    Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, Brazil
  • Peter L Pearson
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Carla Rosenberg
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
  • Nikolai Timchenko
    Department of Surgery, Division of General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  • Ana Cristina Victorino Krepischi
    Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil

抄録

<jats:p>Hepatoblastomas exhibit the lowest mutational burden among pediatric tumors. We previously showed that epigenetic disruption is crucial for hepatoblastoma carcinogenesis. Our data revealed hypermethylation of nicotinamide N-methyltransferase, a highly expressed gene in adipocytes and hepatocytes. The expression pattern and the role of nicotinamide N-methyltransferase in pediatric liver tumors have not yet been explored, and this study aimed to evaluate the effect of nicotinamide N-methyltransferase hypermethylation in hepatoblastomas. We evaluated 45 hepatoblastomas and 26 non-tumoral liver samples. We examined in hepatoblastomas if the observed nicotinamide N-methyltransferase promoter hypermethylation could lead to dysregulation of expression by measuring mRNA and protein levels by real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot assays. The potential impact of nicotinamide N-methyltransferase changes was evaluated on the metabolic profile by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Significant nicotinamide N-methyltransferase downregulation was revealed in hepatoblastomas, with two orders of magnitude lower nicotinamide N-methyltransferase expression in tumor samples and hepatoblastoma cell lines than in hepatocellular carcinoma cell lines. A specific TSS1500 CpG site (cg02094283) of nicotinamide N-methyltransferase was hypermethylated in tumors, with an inverse correlation between its methylation level and nicotinamide N-methyltransferase expression. A marked global reduction of the nicotinamide N-methyltransferase protein was validated in tumors, with strong correlation between gene and protein expression. Of note, higher nicotinamide N-methyltransferase expression was statistically associated with late hepatoblastoma diagnosis, a known clinical variable of worse prognosis. In addition, untargeted metabolomics analysis detected aberrant lipid metabolism in hepatoblastomas. Data presented here showed the first evidence that nicotinamide N-methyltransferase reduction occurs in hepatoblastomas, providing further support that the nicotinamide N-methyltransferase downregulation is a wide phenomenon in liver cancer. Furthermore, this study unraveled the role of DNA methylation in the regulation of nicotinamide N-methyltransferase expression in hepatoblastomas, in addition to evaluate the potential effect of nicotinamide N-methyltransferase reduction in the metabolism of these tumors. These preliminary findings also suggested that nicotinamide N-methyltransferase level may be a potential prognostic biomarker for hepatoblastoma.</jats:p>

収録刊行物

  • Tumor Biology

    Tumor Biology 42 (12), 101042832097712-, 2020-11-30

    IOS Press

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