Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes.
Global loss of DNA methylation is frequently observed in the genome of human tumors. Although this epigenetic alteration is clearly associated with cancer progression, the way it exerts its pro-tumoral effect remains incompletely understood. A remarkable consequence of DNA hypomethylation in tumors is the aberrant activation of "cancer-germline" genes (also known as "cancer-testis" genes), which comprise a diverse group of germline-specific genes that use DNA methylation as a primary mechanism for repression in normal somatic tissues. Here we review the evidence that such cancer-germline genes contribute to key processes of tumor development. Notably, several cancer-germline genes were found to stimulate oncogenic pathways involved in cell proliferation (SSX, DDX43, MAEL, PIWIL1), angiogenesis (DDX53), immortality (BORIS/CTCFL), and metastasis (CT-GABRA3). Others appear to inhibit tumor suppressor pathways, including those controlling growth inhibition signals (MAGEA11, MAGEB2), apoptosis (MAGEA2, MAGEC2), and genome integrity (HORMAD1, NXF2). Cancer-germline genes were also implicated in the regulation of tumor metabolism (MAGEA3/MAGEA6). Together, our survey substantiates the concept that DNA hypomethylation promotes tumorigenesis via transcriptional activation of oncogenes. Importantly, considering their highly restricted pattern of expression, cancer-germline genes may represent valuable targets for the development of anti-cancer therapies with limited side effects.
Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Aurélie
A
Van Tongelen
Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Axelle
A
Loriot
Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. Electronic address: charles.desmet@uclouvain.be.
Charles
C
De Smet
D000818:Animals; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes
D004273:DNA, Neoplasm
Cancer-germline; Cancer-testis; DNA methylation; Epigenetic