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 Table of Contents  
SHORT COMMUNICATION
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 194-198

Targeting epigenetic alterations in the treatment of glioma


Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, Italy

Date of Submission19-Jan-2021
Date of Acceptance16-Feb-2021
Date of Web Publication02-Jun-2021

Correspondence Address:
Dr. Chidiebere Emmanuel Okechukwu
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome.
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_3_21

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  Abstract 

A glioma is a kind of tumor that initiates in the glial cells of the brain or the spinal cord. High rates of complications and mortality are leading features of gliomas, a glioma can be treated through a surgical procedure, radiation, and chemotherapy. This short communication aimed to analyze the crucial role of epigenetic alterations in the pathogenesis of gliomas and the possible treatment of gliomas by manipulating epigenetic mechanisms. The pathogenesis of glioma is associated with key epigenetic mechanisms, which are deoxyribonucleic acid (DNA) methylation, abnormal microribonucleic acid (RNA), chromatin remodeling, and histone modifications. Alterations and mutations in genes are often seen in gliomas. Alterations and mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in gliomas; mutant IDH1 facilitates the maintenance of genomic stability in tumors by increasing the DNA damage reaction. Moreover, therapeutic modification of epigenetic alterations connected with the development of gliomas is of utmost clinical significance; comprehensive knowledge of epigenetic aberrations that lead to the formation of glioma will help in the design and development of epigenetic drugs for the treatment of gliomas. Some medications that target epigenetic alterations such as inhibitors of mutant IDH, bromodomain and extraterminal motif inhibitors, histone deacetylase inhibitor, DNA methylation inhibitors, and enhancer of zeste homolog 2 inhibitors are presently used to tackle glioma.

Keywords: Brain tumor, epigenetic, epigenetic therapies, glioblastoma, glioma, predictive markers


How to cite this article:
Okechukwu CE. Targeting epigenetic alterations in the treatment of glioma. MGM J Med Sci 2021;8:194-8

How to cite this URL:
Okechukwu CE. Targeting epigenetic alterations in the treatment of glioma. MGM J Med Sci [serial online] 2021 [cited 2021 Oct 21];8:194-8. Available from: http://www.mgmjms.com/text.asp?2021/8/2/194/317448




  Introduction Top


A glioma is a kind of tumor that initiates in the glial cells of the brain or the spinal cord; gliomas comprise about 30% of central nervous system tumors and 80% of all cancerous brain tumors.[1] High rates of complications and mortality are prominent features of gliomas, a glioma can be treated through a surgical procedure, radiation, and chemotherapy.[1] The pathogenesis of glioma is associated with key epigenetic mechanisms, which are deoxyribonucleic acid (DNA) methylation, abnormal microribonucleic acid (miRNA), chromatin remodeling, and histone modifications.[1] Alterations and mutations in genes play crucial roles in the pathogenesis of gliomas.[1] Moreover, therapeutic modification of epigenetic alterations connected with the development of gliomas is relevant in the clinical management of gliomas; therefore, a comprehensive knowledge of epigenetic aberrations leading to the formation of gliomas could help in the design of epigenetic drugs for the treatment of gliomas.[2] Alterations and mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in gliomas, and mutant IDH1 facilitates the maintenance of genomic stability in tumors by increasing DNA damage reaction. Patients with IDH1-mutant tumors have a high survival rate, even though IDH1-mutant tumors are less sensitive to radiation when compared with other gliomas.[3] This short communication aimed to analyze the crucial role of epigenetic alterations in the pathogenesis of gliomas and the possible treatment of gliomas by manipulating epigenetic mechanisms.


  Bibliographic search Top


Relevant articles that were written in English, which reported on epigenomic regulators and treatment for gliomas, were selected for this study from the PubMed database. Full articles and relevant data were extracted. The MeSH system was used to extract relevant research studies in PubMed, using the following terms: Glioma; OR Brain tumor; OR Glioblastoma; OR Epigenetic; OR Predictive markers; OR Epigenetic therapies.


  Key epigenetic mechanisms Top


DNA methylation

DNA methylation is a process by which methyl groups are integrated into cytosine molecules by DNA methyltransferases (DNMTs), forming 5-methylcytosine, and augments the suppression of transcription. The human genome contains nearly 29 million 5′—C—phosphate—G—3′ (CpG) dinucleotides; this augments the rise in the information content of the genome and bestows human genomes with the capability to subdue exact sequences to irrevocable transcriptional silencing.[4] Nearly 70% of the CpG dinucleotides within the human genome are methylated, and CpG islands are defined as regions of DNA where the GC content is greater than 60%.[5] DNA methylation prevents transcription by interfering with the binding of transcription factors to recognition sites on promoters or by recruiting and binding transcriptional repressors, methyl-CpG-binding proteins, and altering chromatin structure into an active state.[5] 5-Methylcytosines can also be oxidized to form 5-hydroxymethylcytosine to reduce the interaction of DNA with DNA-binding proteins.[5] CpG methylation may also cause a dual effect on transcription: repressing transcription when CpG methylation occurs at the promotor level or promoting transcription when CpG methylation affects the gene sequence.[6] A family of DNMTs catalyzes the transfer of methyl groups from S-adenosyl-methionine to cytosine in CpGs.[7] In humans, the most prominent de novo DNMTs are DNMT3A and DNMT3B. Generally, there is the DNMT1 that is expressed in neurons and DNMT2 which methylates aspartic acid transfer RNA but does not methylate DNA.[8],[9],[10],[11]

Histone modifications

Histone modifications comprise histone acetylation, methylation, phosphorylation, SUMOylation, ubiquitylation, glycosylation, ADP ribosylation, and biotinylated.[12] These are important epigenetic features, with fundamental roles in biological processes such as transcription, DNA repair, and DNA replication.[12] Histone acetylation is achieved by the action of histone acetyltransferase, which adds an acetyl group to a lysine residue, resulting in chromatin/transcriptional activation.[13] Histone deacetylation is produced by histone deacetylases which remove the acetyl groups and is related to chromatin deactivation and transcriptional repression.[13]

Chromatin remodeling

Consistent heterochromatin is vital for silencing transposable elements and upholding genome integrity; adenosine triphosphate (ATP)-dependent chromatin remodeling complexes use ATP hydrolysis to transfer and rearrange nucleosomes, permitting the accessibility of transcription factors to DNA.[14],[15] Their transcriptional effects which entail either activation or repression rely on the conscription of coactivators or corepressors.[15]

Post-translational histone modifications

Post-translational histone changes include acetylation, ubiquitylation, or SUMOylation at lysine residues, methylation at lysine, arginine, or histidine residues, and phosphorylation at serine, threonine, or tyrosine residues, which affect transcription, DNA replication, and DNA repair.[16] Histone acetylation is catalyzed by histone lysine acetyltransferases, mostly, lysine acetyltransferase 2A, lysine acetyltransferase 2B, lysine acetyltransferase 6, lysine acetyltransferase 7, lysine acetyltransferase 8, E1A Binding Protein P300, and CREB-binding protein/CBP.[17] Histone acetylation is connected with transcriptional activation and open chromatin conformation, in other way round, histone deacetylation is involved in transcriptional repression and closed chromatin structure.[18]

Non-coding RNAs

More than 95% of the eukaryotic genome is transcribed into non-coding RNAs (ncRNAs) and less than 5% is translated.[19] Long ncRNAs are non-protein-coding RNAs; ncRNA-mediated epigenetic regulation depends mainly on long ncRNA interactions with proteins or genomic DNA via RNA secondary structures.[20]

Epigenetics alterations associated with the pathogenesis of glioma

The outcomes of studies conducted regarding the pathogenesis of gliomas showed that gliomas have distinctive epigenetic features that have explained their progression and permitted their categorization into diverse molecular subtypes; alterations in the epigenetic regulatory genes IDH1 or IDH2 and in the histone genes H3F3A or HIST1H3B are important biomarkers for tumor categorization and this highlights the stirring role of epigenetic alterations in the progression of gliomas.[21] A point mutation in IDH1 or IDH2 is a distinctive feature for lower-grade gliomas (grade II/III), which is highly prevalent in young adults.[22] IDH-mutant (IDHmt) gliomas consist of oligodendrogliomas, with codeletion of chromosomal arms 1p/19q (1p/19q codel) which are typically linked with an initiating mutation in the promoter of telomerase reverse transcriptase and astrocytomas without 1p/19q codel.[23] Low-grade gliomas without IDH mutation are termed IDH wild-type (IDHwt) astrocytomas and are deemed provisional component by the 2016 World Health Organization (WHO) classification; upon further genetic assessments, they might be classified into other entities.[24] In glioblastomas, IDHmt is rare and is usually seen in younger patients whose tumors might have evolved from an IDHmt lower-grade glioma WHO grade II or III.[24] The histone mutation H3K27M is a characteristic of pediatrics midline high-grade glioma and the H3G34R/V mutation for hemispheric high-grade glioma in children and young adults.[24] These epigenetic mutations in gliomas are linked to distinctive DNA methylation features, and they exhibit distinctive age-associated distributions pattern and location.[25] The most commonly analyzed epigenetic changes in cancer consist of changes in DNA methylation, particularly methylation at the fifth position of cytosines at CpG sites, causing the formation of 5-methylcytosine or the fifth base of DNA.[26] There are numerous DNA methyltransferases implicated in DNA methylation, of which all utilize S-adenosyl-l-methionine as a supplier of methyl groups.[27] DNMT1 specially methylates hemimethylated DNA and is liable for the protection of DNA methylation patterns during replication, whereas DNMT3A, DNMT3B, and DNMT3L exert their actions on unmethylated DNA and are liable for de novo methylation.[28] DNA demethylation involves the 10-11 translocation (TET) methylcytosine dioxygenases (1–3) that convert 5 methylcytosines to 5-hydroxymethylcytosine.[29] Further epigenetic DNA modifications are known; however, their characteristics are complicated and their function is less studied.[4] Cancer pathogenesis is connected with DNA hypomethylation altering intergenic areas, repetitive DNA sequences, gene bodies, including regulatory sequences, and aberrant de novo methylation of CpG islands in promoter regions of tumor suppressor genes.[4] Epigenetic gene silencing following CpG island methylation is mediated through methyl-CpG-binding domain proteins such as methyl CpG binding protein 2 that recruit histone-modifying and chromatin-remodeling complexes to the methylated sites.[30] DNA methylation profiles of cancerous cells are highly characteristic and retain some traits of the cell of origin.[30] They have been successfully used for re-defining the classification of brain tumors or for determining the origin of metastasis of unknown primary cancer.[30] Aberrant methylation of CpG islands in gene promoters leads to gene silencing affecting pathways linked to cancer.[30] Activation of the Wnt signaling pathways in glioblastomas is facilitated by deviant promoter methylation of numerous undesirable regulators, such as the gene encrypting the Wnt inhibitory factor 1 or the family of secreted frizzled-related proteins and Dickkopf; likewise, negative regulators of the Ras pathway are silenced, such as the Ras association domain family member.[31] Gliomas with mutations in the metabolic genes IDH1 or IDH2 exhibit a noticeable sign of DNA hypermethylation that is different from IDHwt gliomas and has been labeled glioma CpG island methylator phenotype; IDH mutations are initial lesions in the growth of gliomas and constellation in the substrate-binding site of these enzymes, at codon 132 of IDH1 or codon 172 of IDH2.[32] These mutations are heterozygous and upregulate a feasible response catalyzing the conversion of α-ketoglutarate into D-2-hydroxyglutarate (2HG).[33] 2HG is an oncometabolite, it accumulates to high concentrations which hinders α-ketoglutarate-dependent enzymes.[33] α-Ketoglutarate-reliant enzymes consist of epigenetic modifiers such as the enzyme TET2 involved in DNA demethylation or the lysine-specific demethylase 2A, although α-ketoglutarate-dependent enzymes also play important roles in several cellular functions that are inhibited by 2HG, thereby affecting response to chemotherapy.[33] IDH mutations are considered a crucial mechanism for the advancement of glioma CpG island methylator phenotype (G-CIMP) via the formation of 2HG which facilitates DNA hypermethylation through inhibition of TET2.[34] Moreover, IDHmt gliomas irrespective of tumor grade show a different immune phenotype illustrated by decreased expression of immune response and by fewer permeation of tumor-related immune cells; this might be facilitated by numerous mechanisms, such as G-CIMP-connected hypermethylation of immune response associated genes in the tumor, and by down-regulation of leukocyte chemotaxis.[35] The DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is a key epigenetic silenced gene in gliomas; in glioblastomas, methylation of MGMT is a prognostic marker for assessing the progress of temozolomide treatment, and MGMT methylation status has emerged as a key prognostic biomarker.[35] Patients with an unmethylated MGMT essentially do not benefit from temozolomide therapy simultaneously with radiotherapy.[36]

Epigenetic therapy for glioma

The concomitant use of epigenetic drugs with chemo/radiotherapy could be more effective in the treatment of gliomas. Epigenetic drugs such as inhibitors of mutant IDH seem to be effective in obliterating gliomas. Others such as bromodomain and extraterminal motif inhibitors, histone deacetylase inhibitor, DNA methylation inhibitors, and enhancer of zeste homolog 2 inhibitors are currently utilized to treat gliomas; however, a good number of these epigenetic drugs are still undergoing clinical trials.[37],[38],[39],[40],[41] Moreover, a multimodal treatment strategy for gliomas needs to be researched, approved, and implemented.


  Conclusion Top


Alterations in epigenetic regulating genes have been recognized as biomarkers of subtypes of gliomas with different characteristics. The association among DNA methylation, histone post-translational modifications, and general chromatin structural changes enables the decoding of the epigenetic alterations involved in the pathogenesis of gliomas, and this gives a comprehensive idea in the development of diagnostic and therapeutic agents for the treatment of gliomas. Most of the features of gliomas are mutations in IDH1 or IDH2 in lower-grade gliomas and histone 3 mutations in pediatric high-grade gliomas which are associated with DNA methylation patterns. Some medications that target epigenetic alterations such as inhibitors of mutant IDH, bromodomain and extraterminal motif inhibitors, histone deacetylase inhibitor, DNA methylation inhibitors, and enhancer of zeste homolog 2 inhibitors are presently used to tackle glioma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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