Targeting of Histone Demethylases KDM5A and KDM6B Inhibits the Proliferation of Temozolomide-Resistant Glioblastoma Cells.

Massimo Romani,Antonio Daga,Maria Pia Pistillo,Alessandra Forlani,Barbara Banelli

doi:10.3390/cancers11060878

Abstract

Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG. The aim of our work was to determine if GSK J4 could be effective against GB cells that have acquired TMZ resistance and if it could synergize with TMZ or JIB 04 to increase the clinical utility of these molecules. Standard functional and pharmacological analytical procedures were utilized to determine the efficacy of the molecules under study when used alone or in combination against native GB cells and in a model of drug resistance. The results of this study indicated that although GSK J4 is active against native and TMZ-resistant cells, it does so at a lower efficacy than JIB 04. Drug combination studies revealed that GSK J4, differently from JIB 04, does not synergize with TMZ. Interestingly, GSK J4 and JIB 04 strongly synergize and are a potent combination against TMZ-resistant cells. Further studies in animal models will be necessary to determine if this combination of molecules might foster the development of novel therapeutic approaches for glioblastoma.

Highlights

Histone methylation is a post-synthetic modification of selected lysine of histones H3 and H4 that was discovered along with histone acetylation in the last century [1] and, in conjunction with other histone modifications and DNA methylation, participate in chromatin remodeling [2]
Histone lysine methylation is associated with transcriptionally active or inactive chromatin regions depending on the residue that is modified, and the effect of this modification on transcription is finely tuned by the extent of methylation and from the synergic or antagonist interaction with other modifications [2,3]
With the discovery of the amine oxidase LSD1 or, according to the current nomenclature, KDM1 [4], it became clear that histone lysine methylation is fully reversible, and we know that this modification is regulated by more than 30 different enzymes with distinct specificities [5,6]

Summary

Introduction

Histone methylation is a post-synthetic modification of selected lysine of histones H3 and H4 that was discovered along with histone acetylation in the last century [1] and, in conjunction with other histone modifications and DNA methylation, participate in chromatin remodeling [2]. Histone lysine methylation is associated with transcriptionally active or inactive chromatin regions depending on the residue that is modified, and the effect of this modification on transcription is finely tuned by the extent of methylation (mono-, di-, or trimethylation) and from the synergic or antagonist interaction with other modifications [2,3]. From other histone modifications, lysine methylation does not change the net charge of the histone tail; the interaction with the DNA was long considered to be an irreversible modification. Histone methylation, along with other epigenetic modifications, is deeply involved in the mechanisms of drug resistance, and in one of the leading causes of failure of cancer therapy [5,13,14,15,16,17]

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