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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>","DOI":"10.1177\/1010428320977124","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T02:39:22Z","timestamp":1606790362000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":20,"title":["Hepatoblastomas exhibit marked\n                    <i>NNMT<\/i>\n                    downregulation driven by promoter DNA hypermethylation"],"prefix":"10.1177","volume":"42","author":[{"given":"Maria Prates","family":"Rivas","sequence":"first","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talita Ferreira Marques","family":"Aguiar","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-3186","authenticated-orcid":false,"given":"Mariana","family":"Maschietto","sequence":"additional","affiliation":[{"name":"Research Center, Boldrini Children\u2019s Hospital, Campinas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renan B","family":"Lemes","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz Carlos","family":"Caires-J\u00fanior","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Goulart","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayque Alves","family":"Telles-Silva","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-4845","authenticated-orcid":false,"given":"Estela","family":"Novak","sequence":"additional","affiliation":[{"name":"Pediatric Cancer Institute (ITACI) at the Pediatric Department, S\u00e3o Paulo University Medical School, S\u00e3o Paulo, Brazil"},{"name":"Molecular Genetics\u2014S\u00e3o Paulo\u2019s Blood Center, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian Maria","family":"Cristofani","sequence":"additional","affiliation":[{"name":"Pediatric Cancer Institute (ITACI) at the Pediatric Department, S\u00e3o Paulo University Medical School, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Odone","sequence":"additional","affiliation":[{"name":"Pediatric Cancer Institute (ITACI) at the Pediatric Department, S\u00e3o Paulo University Medical School, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Cypriano","sequence":"additional","affiliation":[{"name":"Department of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Regina Caminada","family":"de Toledo","sequence":"additional","affiliation":[{"name":"Department of Pediatric, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirce Maria","family":"Carraro","sequence":"additional","affiliation":[{"name":"International Center for Research, A.C. 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