Suchergebnisse

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

Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma. ; This work has been financially supported by: the Plan Nacional de I+D+I 2013-2016/FEDER (PI15/00892 to M.F.F. and A.F.F.); the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, and the Plan Nacional de I+D+I 2008-2011/FEDER (CP11/00131 to A.F.F.); IUOPA (to G.F.B., M.I.S. and C.M.); the Fundación Científica de la AECC (to R.G.U.); FICYT (to M.G.G. and A.C.); and the Asturias Regional Government (GRUPIN14-052 to M.F.F.). A.F.F. is also supported from Ministerio de Economía y Competitividad and the European Regional Development Fund (FEDER), Programa Retos de la Sociedad 2015 (RTC-2015-3393-1). The IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain. ; Peer Reviewed