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

Abstract

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 although 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 is associated with KMT5B downregulation and genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Ectopic overexpression of KMT5B 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 a subset of deregulated genes, thus suggesting a possible role for KMT5B in GBM through the epigenetic modulation of key target cancer genes. ; This research was funded by the Health Institute Carlos III (Plan Nacional de I+D+I) cofounding FEDER (PI15/00892 and PI18/01527 to MF and AF); the Government of the Principality of Asturias PCTI-Plan de Ciencia, Tecnología e Innovación de Asturias co-funding 2018–2022/FEDER (IDI/2018/146 to MF); AECC (PROYE18061FERN to MF); FGCSIC (0348_CIE_6_E to MF); Severo Ochoa Program BP17-165 to PS-O and BP17-114 to RP); the Ministry of Economy and Competitiveness of Spain (VL, Juan de la Cierva fellowship IJCI-2015-23316; JT, Juan de la Cierva fellowship FJCI-2015-26965); FICYT (AC and MG); FINBA-ISPA (VL); and IUOPA (VL and CM). The IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain. ; Peer reviewed