AUTHOR=Rivas Maria Prates , Aguiar Talita Ferreira Marques , Fernandes Gustavo Ribeiro , Caires-Júnior Luiz Carlos , Goulart Ernesto , Telles-Silva Kayque Alves , Cypriano Monica , de Toledo Silvia Regina Caminada , Rosenberg Carla , Carraro Dirce Maria , da Costa Cecilia Maria Lima , da Cunha Isabela Werneck , Krepischi Ana Cristina Victorino 

TITLE=TET Upregulation Leads to 5-Hydroxymethylation Enrichment in Hepatoblastoma

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00553

DOI=10.3389/fgene.2019.00553

ISSN=1664-8021

ABSTRACT=<p>Hepatoblastoma is an embryonal liver tumor carrying few genetic alterations. We previously disclosed in hepatoblastomas a genome-wide methylation dysfunction, characterized by hypermethylation at specific CpG islands, in addition to a low-level hypomethylation pattern in non-repetitive intergenic sequences, in comparison to non-tumoral liver tissues, shedding light into a crucial role for epigenetic dysregulation in this type of cancer. To explore the underlying mechanisms possibly related to aberrant epigenetic modifications, we evaluated the expression profile of a set of genes engaged in the epigenetic machinery related to DNA methylation (<italic>DNMT1</italic>, <italic>DNMT3A</italic>, <italic>DNMT3B</italic>, <italic>DNMT3L</italic>, <italic>UHRF1</italic>, <italic>TET1</italic>, <italic>TET2</italic>, and <italic>TET3</italic>), as well as the 5-hydroxymethylcytosine (5hmC) global level. We observed in hepatoblastomas a general disrupted expression of these genes from the epigenetic machinery, mainly <italic>UHRF1</italic>, <italic>TET1</italic>, and <italic>TET2</italic> upregulation, in association with an enrichment of 5hmC content. Our findings support a model of active demethylation by <italic>TETs</italic> in hepatoblastoma, probably during early stages of liver development, which in combination with <italic>UHRF1</italic> overexpression would lead to DNA hypomethylation and an increase in overall 5hmC content. Furthermore, our data suggest that decreased 5hmC content might be associated with poor survival rate, highlighting a pivotal role of epigenetics in hepatoblastoma development and progression.</p>