Epigenetic-Based Therapy-A Prospective Chance for Medulloblastoma Patients' Recovery

Abstract

Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient's age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system's function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate.

Keywords: DNA methylation; DNA methyltransferase inhibitors; bromodomain; epigenetics; histone deacetylases inhibitors; lncRNA; medulloblastoma; miRNA; targeted therapy.

Figure 1

(A) Cytidine and its analogs (B) 5AC and (C) DAC. An additional nitrogen atom (marked in red) is responsible for the inhibitory activity of these molecules toward DNMTs.

Figure 2

Major DNMTis effects on MB cells. (A) The transcription of TSGs is induced by DNMTi-dependant hypomethylation of the gene’s promoter. Encoded proteins regulate cell proliferation. (B) In contrast, DNMTi-induced hypomethylation of the gene’s body stops the translation process. In the case of oncogenes, which encode proteins that induce cell proliferation, such hypomethylation induces apoptosis.

Figure 3

The chemical structures of quinoline-based DNMTis. (A) MC3343: one of the first non-nucleoside DNMTis tested in a cancer stem cell line. (B) MC3353: a novel, more potent compound.

Figure 4

Comparison between treatments with MS-275, Doxorubicin, and their combination, leading to the apoptosis of the MB cells. Monotherapy with Doxorubicin causes the acetylation and nuclear accumulation of p53, which induces Bax expression. Bax protein then oligomerizes to the mitochondrial outer membrane, causing cytochrome c release, which induces apoptosis. Acetylation of the Ku70 protein with MS-275 releases Bax and leads to apoptosis. Combined treatment with Doxorubicin and MS-275 shows a synergistic apoptotic effect. It promotes the binding of p53 to Bax, leading to Bax activation and the loss of mitochondrial membrane potential, as well as greater DNA damage. Ku70, acetylated by MS-275, has reduced DNA repair activity. Thus, DNA strand breaks caused by the Doxorubicin are left unrepaired.

Figure 5

Visualization of the bromodomain and extra-terminal domain (BET) contribution in transcription initialization (A) and its suppression in the presence of BET inhibitors (B).