**5. Epigenetics in human gliomas with some details**

Acetylation of lysine residues is a post-tranlational modification controlled by the opposing action of histone deacetylases (HDACs) and histone acetyl transferases (HATs) [58–60]. Histone methylation may generally occur on the side chains of lysines and arginines, which can alter the activity of effector proteins of the transcriptional machinery [58–60]. It has been reported that some mutations in some regulatory genes such as HDACs (HDAC2 and HDAC9), histone demethylases (JMJD1A and JMJD1B), and histone methyltransferases (SET7, SETD7, MLL, MLL3, and MLL4) have been detected to a large extent in genomic analysis of GBM samples [34]. However, it is still unclear whether histone modifications play signifi‐ cant roles in gliomas and their potential can serve as biomarkers and/or therapeutic targets. Noncoding RNAs are known to play an important role in the epigenetic regulation of gene expression [61,62].

is a correlation between p53 and GBM prognosis is still unclear due to the complexity of the p53 signaling pathway. P53 pathway includes many important regulators and the heteroge‐ neity of p53 mutation types can also affect the p53 molecule. Because of those mentioned,

The deletion of 1p and 19q, occurring early in tumorigenesis, is known as an important genetic signature. The deletion is seen in 50–70% of patients with low-grade oligodendrogliomas. This can be predictive for the tumor's chemosensitivity to some agents [46,47]. It has been report‐ ed that *P190RhoGAP*, localized on 19q13.3, can be one of the candidate genes as a tumor suppressor [48]. A large-scale genomic analysis by array CGH has reported two different patterns about 1p deletion for prognostic factors. One of them is the whole 1p (associated with the deletion of the whole 19q). This may be associated with a good prognosis for oligoden‐ drogliomas. Another is 1p deletion (not associated with 19q loss). This deletion has a nega‐ tive prognostic value and improves progression-free survival (PFS) and overall survival (OS). It is mostly associated with astrocytomas [49]. It is also related to the response to chemother‐ apy and radiation in oligodendroglioma. Data obtained from EORTC 26951 and RTOG 9402 trials showed an improvement in OS with the addition of radiation to procarbazine/lomus‐ tine/vincristine chemotherapy in anaplastic oligodendroglioma with 1p/19q mutation [50]. There are some studies correlated with these similar findings, In GBM, similar findings have been demonstrated in some studies [51,52], but not in others [53,54]. It has also been report‐ ed that codeletion of 1p and 19q is related with *IDH1* mutation and *MGMT* hypermethyla‐

O-6-Methylguanine-DNA-methyltransferase (MGMT) is involved in removal of alkylation at the O6 position of guanine. Hypermethylation of *MGMT* transcriptionally down-regulated its expression. This situation results in impaired repair capability response to chemotherapeutic agents and radiation. Some clinical trials have confirmed the prognostic and predictive roles of *MGMTm* [56]. It has been suggested that patients with *MGMTm* are responsive to chemo‐ therapy. However, *MGMT* status was not distinguished between patients with glioblastoma (GBM) and those with anaplastic astrocytoma (AA) and this restricts interpretation of the study. The European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981 and National Cancer Institute of Canada (NCIC) trials also indicates increased responsiveness to temozolomide for patients with MGMTm [57]. It has been suggested that a standard marker both following prognosis and identifying patients for clinical trials, in which alkylation therapies and/or radiation therapy are applied, may be used for MGMTm [1].

Acetylation of lysine residues is a post-tranlational modification controlled by the opposing action of histone deacetylases (HDACs) and histone acetyl transferases (HATs) [58–60]. Histone methylation may generally occur on the side chains of lysines and arginines, which can alter the activity of effector proteins of the transcriptional machinery [58–60]. It has been

**5. Epigenetics in human gliomas with some details**

therapies targeting P53 have been limited in this field [42].

152 Neurooncology - Newer Developments

tion [47,55].

One group ofRNAs are described as microRNAs (miRNAs). miRNAs are importantregulators for gene expression. miRNAs post-transcriptionally regulate expression of target genes. miRNAs are double-stranded RNA molecules of approximately 22 nucleotides (nt) in length. miRNA binds to specific recognition sequences within the 3'-untranslated region (3'-UTR) of target mRNAs [61–63]. miRNAs are characterized functionally into tumor suppressors and oncogenic miRNAs. Tumor suppressor miRNAs are frequently down-regulated in gliomas as compared to normal brain [64–67]. In contrast, some miRNAs are defined as oncogenes with enhanced expression in glioma such as miR-21, targeting regulators, miR-10b and miR-221, targeting cell cycle inhibitors, miR-30e, and targeting IjBa [68–71]. It has been suggested that there is a link between miRNAs and well-known stem cell-regulating proteins [72]. It has also been reported that miR-17-92 plays a critical role in regulation of glioma stem cell (GSC) differentiation, apoptosis, and proliferation [73]. miR-451 expression reduced notably in cancer cells kept in low glucose conditions. Results revealed that cancer cells kept in low glucose conditions had reduced cell proliferation but an enhanced rate of cell migration and survival in glioblastomas. Glucose sufficiency induced upregulation of miR-451 notably inhibited LKB1/AMPK pathway activation [74]. miR-128, downregulated in glioblastoma tissue, has a tumor-suppressive function. Both in vitro and in vivo, miR-128 expression significantly reduces glioma cell proliferation via downregulation of *Bmi-1 oncogene*, a component of the polycomb repressor complex (PRC). In addition, miR-128 inhibits GSC self-renewal [75]. The PRC has been shown to induce normal and cancer stem cell self-renewal and plays role in GSC regulation [76]. When miR-124 has overexpression, it can inhibit the CD133+ cell subpopulation of the neurosphere and downregulate stem cell markers, such as *BMI1*, *Nanog*, and *Nestin* [77]. Both miR-124 and miR-137 are up-regulated during adult neural stem cell differentiation and down-regulated in high-grade gliomas [78]. Although there are comprehensive studies about miRNa in gliomas, it should not be forgotten that one miRNA can affect the expression of various target genes. It must be reconsidered in terms of several important aspects before miRNAs may be used therapeutically [79].

LncRNAs which have more than 200 nucleotides and are up to 100 kb in length are described as an important RNA molecule that plays role in some biological cellular actions such as stemness, development, and cell survival [80–82]. Maternally expressed gene 3 (*MEG3*) is a maternally expressed imprinted gene that can also act as an lncRNA. Its expression in glioma tissues is lower than that in normal adjacent tissues [83]. The tumor-suppressive role of *MEG3* is confirmed by the fact that it can associate with p53. It is known that this association is needed for p53 activation [84].
