The epigenetic mechanisms involved in the treatment resistance of glioblastoma

Abstract

Glioblastoma (GBM) is an aggressive malignant brain tumor with almost inevitable recurrence despite multimodal management with surgical resection and radio-chemotherapy. While several genetic, proteomic, cellular, and anatomic factors interplay to drive recurrence and promote treatment resistance, the epigenetic component remains among the most versatile and heterogeneous of these factors. Herein, the epigenetic landscape of GBM refers to a myriad of modifications and processes that can alter gene expression without altering the genetic code of cancer cells. These processes encompass DNA methylation, histone modification, chromatin remodeling, and non-coding RNA molecules, all of which have been found to be implicated in augmenting the tumor's aggressive behavior and driving its resistance to therapeutics. This review aims to delve into the underlying interactions that mediate this role for each of these epigenetic components. Further, it discusses the two-way relationship between epigenetic modifications and tumor heterogeneity and plasticity, which are crucial to effectively treat GBM. Finally, we build on the previous characterization of epigenetic modifications and interactions to explore specific targets that have been investigated for the development of promising therapeutic agents.

Keywords: DNA methylation; epigenetics; glioblastoma; histone modification; miRNA; treatment resistance; tumoral heterogeneity.

Figure 1

Illustration of the different epigenetic modifications that target chromatin and contribute to treatment resistance in GBM. (A) DNA methylation silences the promoters of tumor suppressor genes, hence contributing to the proliferative ability of GBM cells. This mechanism also has the ability to suppress the expression of inhibitors of the WNT pathway (WIF1, DKKF, NKD, sFRP) and RAS pathway (RASSF1A); (B) Histone acetylation, which is achieved by histone acetylases and reversed by histone deacetylases, can also contribute to the regulation of chromatin structure and gene expression. For example, histone acetylation by KAT6A can lead to increased expression of the genes involved in the overactivation of the PI3K/AKT oncogenic pathway. This is reversed by the histone deacetylase HDAC1; (C) Histone methylation is another alteration that can control the expression of genes. For instance, the interplay between the histone methylase MLL and the demethylase KDM1 can regulate the expression of HOX genes, which are implicated in cancer proliferation and treatment resistance; (D) The chromatin remodeling complex SWI/SNF can alter the architecture of chromatin through several of its domains. One such domain, ACTL6A, can promote the expression of the YAP/TAZ pathway, which, in turn, contributes to treatment resistance. GBM: Glioblastoma multiforme; MGMT: methylguanine methyltransferase; PTEN: phosphatase and tensin homolog; WNT: wingless; WIF: WNT inhibitory factor; DKKF: dickkopf; NKD: naked cuticle; sFRP: secreted frizzled-related protein family; RASSF1: ras association domain family; HDAC: histone deacetylase; KAT: lysine acyltransferase; MLL: mixed lineage leukemia; KDM: histone lysine demethylase; SWI/SNF: switch/sucrose non-fermentable; ACTL6A: actin-like protein 6A; PI3K/AKT: phosphoinositide-3-kinase-protein kinase B; HOX: homeobox; YAP/TAZ: yes-associated protein/transcriptional co-activator with PDZ-binding motif.

Figure 2

Non-coding RNAs involved in the development of temozolomide resistance in GBM. Under regular conditions, miR-29c binds to the mRNA of SP1 and induces its degradation. However, the downregulation of miR-29c in GBM leads to increased abundance in SP1 mRNA and elevated SP1 protein expression, which in turn induces the expression of the MGMT gene. Additionally, the overexpression of the lncRNA TALC leads to a decreased abundance of miR-20b-3p. This attenuates the inhibition that miR-20b-3p exerts over the expression of c-MET, resulting in c-MET overexpression and subsequent downstream signaling to augment MGMT expression. The increased MGMT expression induced by these mechanisms ultimately augments the GBM cells’ ability to resist treatment with TMZ. c-MET: Cellular mesenchymal-epithelial transition factor; GBM: glioblastoma; lncRNA: long non-coding RNA; mRNA: messenger RNA; MGMT: O6-methylguanine-DNA methyltransferase; miRNA: microRNA; SP1: specificity protein 1; TMZ, temozolomide.