Epigenetic deregulation of the histone methyltransferase KMT5B contributes to malignant transformation in glioblastoma. Epigenetic deregulation of KMT5B in glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adulthood. Epigenetic mechanisms are known to play a key role in GBM. However, the involvement of histone methyltransferase KMT5B and its mark H4K20me2 has remained largely unexplored. The present study shows that DNA hypermethylation and loss of DNA hydroxymethylation impair KMT5B expression and lead to a genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Restoration of KMT5B expression induced tumor suppressor-like features in vitro and in a mouse tumor xenograft model, as well as changes in the expression of several glioblastoma-related genes. H4K20me2 enrichment was found immediately upstream of the promoter regions of selected up- and down-regulated genes, thus confirming KMT5B-mediated transcriptional regulation. These findings suggest a possible role for KMT5B deregulation in GBM through the epigenetic modulation of key target cancer genes in this tumor type.