A novel cancer-germline transcript carrying pro-metastatic miR-105 andTET-targeting miR-767 induced by DNA hypomethylation in tumors

• DOI: 10.4161/epi.29628
• Publication Date: 2014-06-19T16:12:03Z
• Authors: Axelle Loriot; Aurélie Van Tongelen; Jordi Blanco; Simon Klaessens; Julie Cannuyer; Nicolas van Baren; Anabelle Decottig...; Charles De Smet
• Keywords: 0301 basic medicine; DNA Methylation; Receptors, GABA-A; Dioxygenases; Mixed Function Oxygenases; 3. Good health; DNA-Binding Proteins; MicroRNAs; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Proto-Oncogene Proteins; Humans; RNA, Messenger; Neoplasm Metastasis; Research Paper

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.