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.
Highlights
Glioblastoma multiforme (GBM) is a malignant grade IV glioma which represents the most common and aggressive primary brain tumor among adults
We found that KMT5B, a gene encoding a histone methyltransferase, had altered DNA methylation and hydroxymethylation patterns
The present study aimed to investigate the contribution of this chromatin modifying gene to the etiology of GBM
Summary
Glioblastoma multiforme (GBM) is a malignant grade IV glioma which represents the most common and aggressive primary brain tumor among adults. Epigenetic alterations affect different types of cancer-related genes involved in cell cycle control, DNA repair, apoptosis, or cell signaling (Feinberg et al, 2016), among others. They can occur at epigenetic regulator genes, thereby triggering a chain of genome-wide massive epigenetic alterations. As examples of the latter are, on the one hand, epigenetic disruption through the downregulation of different micro RNAs that modulate histone deacetylases (HDACs) expression has been reported in several cancers, such as hepatocellular carcinoma (Yuan et al, 2011), lymphoplasmacytic lymphoma (Roccaro et al, 2010), tongue squamous cell carcinoma (Kai et al, 2014), and breast cancer (Wu et al, 2014). Our laboratory has demonstrated that the expression of the epigenetic enzyme TET3 is aberrantly downregulated in GBM through epigenetic mechanisms, leading to a genome-wide reduction of 5-hydroxymethylcytosine (5hmC) levels (Carella et al, 2020)
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