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.

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

“…found that the changes in gene expression of various methyltransferases, acetyltransferases, and deacetylases promoted the pathogenesis of GBM 189 . The nuclear expression levels of lysine methyltransferases SETDB1, KMT5B, Suv‐39h1, and EZH2 in GBM are up‐regulated, compared with normal tissues, and correlated with advanced histological grades 190–193 . Besides, the inhibition of LSD1 in GBM has been discovered by Chandra et al.…”

“…189 The nuclear expression levels of lysine methyltransferases SETDB1, KMT5B, Suv-39h1, and EZH2 in GBM are upregulated, compared with normal tissues, and correlated with advanced histological grades. [190][191][192][193] Besides, the inhibition of LSD1 in GBM has been discovered by Chandra et al to sensitize cells to HDACIs, so LSD1 and HDAC can work together to regulate cell death in GBM cell lines. 194 Besides, patients with higher KDM5B levels in GBM usually have poorer overall survival rates and can promote cancer cell proliferation by regulating p21 expression.…”

Epigenetic Mechanisms of Aging and Aging-Associated Diseases

“…Frequently in cancer, including GBM [ 120 ], there is abnormal methylation level at lysine 20 of histone H4 (H4K20me) [ 121 ].…”

“…Studies of genome-wide disclosed that the gene encoding the histone methyltransferase KMT5B (alias SUV420H1) presents frequently hypermethylated and hypo-hydroxymethylated of DNA in GBM [ 121 , 122 ].…”

“…It was reported that a KMT5B epigenetic downregulation in GBM determines an aberrant H4K20 methylation pattern that may cause global transcriptomic changes, promoting tumor growth [ 121 ].…”