title: A novel cancer-germline transcript carrying pro-metastatic miR-105 and TET-targeting miR-767 induced by DNA hypomethylation in tumors.
abstract: Genome hypomethylation is a common epigenetic alteration in human tumors, where it often leads to aberrant activation of a group of germline-specific genes, commonly referred to as "cancer-germline" genes. The cellular functions and tumor promoting potential of these genes remain, however, largely uncertain. Here, we report identification of a novel cancer-germline transcript (CT-GABRA3) displaying DNA hypomethylation-dependent activation in various tumors, including melanoma and lung carcinoma. Importantly, CT-GABRA3 harbors a microRNA (miR-105), which has recently been identified as a promoter of cancer metastasis by its ability to weaken vascular endothelial barriers following exosomal secretion. CT-GABRA3 also carries a microRNA (miR-767) with predicted target sites in TET1 and TET3, two members of the ten-eleven-translocation family of tumor suppressor genes, which are involved in the conversion of 5-methylcytosines to 5-hydroxymethylcytosines (5hmC) in DNA. Decreased TET activity is a hallmark of cancer; here, we provide evidence that aberrant activation of miR-767 contributes to this phenomenon. We demonstrate that miR-767 represses TET1/3 mRNA and protein expression and regulates genomic 5hmC levels. Additionally, we show that high CT-GABRA3 transcription correlates with reduced TET1 mRNA levels in vivo in lung tumors. Together, our study identified a cancer-germline gene that produces microRNAs with oncogenic potential. Moreover, our data indicate that DNA hypomethylation in tumors can contribute to reduced 5hmC levels via activation of a TET-targeting microRNA.
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Axelle
authors.initials: A
authors.lastname: Loriot
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Van Tongelen
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Jordi
authors.initials: J
authors.lastname: Blanco
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Klaessens
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Cannuyer
authors.affiliation: Ludwig Institute for Cancer Research Ltd; Centre du Cancer des Cliniques; Universitaires Saint-Luc; Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Baren
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Anabelle
authors.initials: A
authors.lastname: Decottignies
authors.affiliation: Group of Genetics and Epigenetics; de Duve Institute; Université Catholique de Louvain; Brussels, Belgium.
authors.forename: Charles
authors.initials: C
authors.lastname: De Smet
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C546257:GABRA3 protein, human; C000599424:MIRN-767 microRNA, human; C588223:MIRN105 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D049308:Dioxygenases
keywords: Cancer epigenetics; DNA methylation; TET genes; cancer-germline or cancer-testis genes; microRNAs
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