A Comprehensive Review of miRNAs and Their Epigenetic Effects in Glioblastoma

Abstract

Glioblastoma is the most aggressive form of brain tumor originating from glial cells with a maximum life expectancy of 14.6 months. Despite the establishment of multiple promising therapies, the clinical outcome of glioblastoma patients is abysmal. Drug resistance has been identified as a major factor contributing to the failure of current multimodal therapy. Epigenetic modification, especially DNA methylation has been identified as a major regulatory mechanism behind glioblastoma progression. In addition, miRNAs, a class of non-coding RNA, have been found to play a role in the regulation as well as in the diagnosis of glioblastoma. The relationship between epigenetics, drug resistance, and glioblastoma progression has been clearly demonstrated. MGMT hypermethylation, leading to a lack of MGMT expression, is associated with a cytotoxic effect of TMZ in GBM, while resistance to TMZ frequently appears in MGMT non-methylated GBM. In this review, we will elaborate on known miRNAs linked to glioblastoma; their distinctive oncogenic or tumor suppressor roles; and how epigenetic modification of miRNAs, particularly via methylation, leads to their upregulation or downregulation in glioblastoma. Moreover, we will try to identify those miRNAs that might be potential regulators of MGMT expression and their role as predictors of tumor response to temozolomide treatment. Although we do not impact clinical data and survival, we open possible experimental approaches to treat GBM, although they should be further validated with clinically oriented studies.

Keywords: DNA methylation; epigenetics; glioblastoma; miRNA; temozolomide.

Figure 1

A flow chart of miRNAs replacement therapy, as a candidate experimental approach, but not yet used for therapy against GBM.

Figure 2

A flowchart of miRNA-based oligonucleotide therapy as a candidate experimental approach but not yet used for therapy against GBM.

Figure 3

Overview of MGMT-TMZ relationship and possible experimental treatments against GBM: (a) Response to TMZ in GBM and role of epigenetic modifications: TMZ is a chemotherapeutic drug that kills tumor cells by methylating DNA at O6 and N7 position of guanine and at N3 position of adenine. However, TMZ efficacy is often limited by the DNA repair enzyme MGMT. Hypermethylation at the promoter region of MGMT can restore TMZ cytotoxic effect. (b) MiRNA and epigenetic regulation of glycolytic enzymes that are critical for GBM pathophysiology; PKM2, HK2, and LDHA are the glycolytic enzymes that are aberrantly expressed in glioma patients and strongly influenced by miRNA and epigenetic factors. HK2 hypermethylation exacerbates GBM progression, an effect that can be suppressed by inhibiting DNMT (DNA methyltransferases) with decitabine. On the other hand, hypermethylation of LDHA impedes GBM growth. PKM2 is regulated by both miRNAs as well as epigenetic factors. When hypomethylated by DNMT, PKM2 contributes to the growth and aggressiveness of GBM. Contrary to it, when PKM2 is targeted by miR-7, let-miR-7 and miR-326 repression of glioma is produced. (c) A possible interplay of non-clinical yet experimental possibilities of treatment against GBM.

Figure 3

Overview of MGMT-TMZ relationship and possible experimental treatments against GBM: (a) Response to TMZ in GBM and role of epigenetic modifications: TMZ is a chemotherapeutic drug that kills tumor cells by methylating DNA at O6 and N7 position of guanine and at N3 position of adenine. However, TMZ efficacy is often limited by the DNA repair enzyme MGMT. Hypermethylation at the promoter region of MGMT can restore TMZ cytotoxic effect. (b) MiRNA and epigenetic regulation of glycolytic enzymes that are critical for GBM pathophysiology; PKM2, HK2, and LDHA are the glycolytic enzymes that are aberrantly expressed in glioma patients and strongly influenced by miRNA and epigenetic factors. HK2 hypermethylation exacerbates GBM progression, an effect that can be suppressed by inhibiting DNMT (DNA methyltransferases) with decitabine. On the other hand, hypermethylation of LDHA impedes GBM growth. PKM2 is regulated by both miRNAs as well as epigenetic factors. When hypomethylated by DNMT, PKM2 contributes to the growth and aggressiveness of GBM. Contrary to it, when PKM2 is targeted by miR-7, let-miR-7 and miR-326 repression of glioma is produced. (c) A possible interplay of non-clinical yet experimental possibilities of treatment against GBM.