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

多形性胶质母细胞瘤（Glioblastoma multiforme, GBM）是成人最常见且恶性程度最高的脑肿瘤。表观遗传机制在GBM的发生发展中发挥关键作用，这一点已得到学界共识。然而，组蛋白甲基转移酶KMT5B及其介导的修饰标记H4K20me2在该病中的作用仍未得到充分探索。本研究发现，相较于非肿瘤标本，在一批人类GBM样本及细胞系中，DNA高甲基化与DNA羟甲基化缺失会抑制KMT5B的表达，并导致全基因组范围内H4K20me2水平的降低。恢复KMT5B的表达可在体外实验及小鼠肿瘤异种移植模型中诱导出抑瘤样表型，并改变多个胶质母细胞瘤相关基因的表达水平。研究人员在筛选得到的差异表达基因的启动子区域紧邻上游位置检测到H4K20me2的富集，从而证实了KMT5B介导的转录调控作用。上述研究结果表明，KMT5B表达失调可能通过表观遗传调控该肿瘤类型中的关键靶癌基因，进而在多形性胶质母细胞瘤的发生发展中发挥潜在作用。