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 Table of Contents  
REVIEW
Year : 2015  |  Volume : 1  |  Issue : 4  |  Page : 123-130

Promoter Methylated Tumor Suppressor Genes in Glioma


1 Cipher Ground, North Brunswick, NJ, USA
2 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
3 Department of Urology, School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA

Date of Submission02-Aug-2015
Date of Acceptance10-Aug-2015
Date of Web Publication27-Aug-2015

Correspondence Address:
Dr. Yingduan Cheng
Cipher Ground, 675 Rt. 1 South, North Brunswick, NJ 08902
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.163803

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  Abstract 

Epigenetic silencing of tumor suppressor genes (TSGs) is critical for glioma initiation and progression. Emerging reports suggest that increased numbers of TSGs, which are critical to cell cycle, proliferation, apoptosis, migration, invasion, DNA repair, and signaling pathways, were silenced in gliomas. Tumor-specific methylation of TSGs in glioma indicates that they could be used as epigenetic biomarkers for molecular diagnosis and therapeutics. This review summarizes the recent discoveries of epigenetically silenced TSGs in human gliomas, providing better understanding of disrupted epigenetic regulation in glioma progression.

Keywords: DNA methylation, glioma, tumor suppressor gene


How to cite this article:
Cheng Y, Tu Y, Liang P. Promoter Methylated Tumor Suppressor Genes in Glioma. Cancer Transl Med 2015;1:123-30

How to cite this URL:
Cheng Y, Tu Y, Liang P. Promoter Methylated Tumor Suppressor Genes in Glioma. Cancer Transl Med [serial online] 2015 [cited 2019 Oct 23];1:123-30. Available from: http://www.cancertm.com/text.asp?2015/1/4/123/163803


  Introduction Top


In adults, glioma is the most common malignancy of the central nervous system. [1] Based on the specific type of cells with which they share histological features, gliomas have several main types: ependymomas (ependymal cells), astrocytomas (astrocytes), and oligodendrogliomas (oligodendrocytes). [2] According to WHO classification of brain tumors, gliomas are further classified into low-grade (Grades I and II), and high-grade (Grades III and IV) tumors. [3] Grade IV glioblastoma (GBM) is the most devastating malignant form of glioma with a median overall survival of 14.6 months despite the continuous progress in therapeutic technologies, including surgery, radiotherapy, photodynamic therapy, and chemotherapy. [3],[4] Around 60% of the high-grade gliomas are GBMs, the incidence rate of which is approximately 3/100,000. [5] Understanding of the molecular mechanisms, and early detection of this malignant tumor are critical for a successful therapy.

The development of a tumor from a normal cell is a complex and multi-step process. A large number of oncogenes, tumor suppressor genes (TSGs), and signaling transduction pathways are involved in this process. [6],[7] It is well accepted that carcinogenesis is driven by the accumulation of genetic and epigenetic changes, which result in the uncontrollable balance between cell proliferation and cell death. [7] Aberrant epigenetic mechanisms, such as DNA methylation, histone modification, nucleosome positioning, noncoding RNA, and microRNAs are recognized as key events in cancer development. Currently, it is well accepted that epigenetic alterations even precede the genetic changes during tumorigenesis. [8] Many epigenetic silenced functional TSGs are identified in multiple tumors, and these genes could function as biomarkers for cancer diagnosis. [9],[10],[11],[12],[13],[14] Hypermethylated TSGs in cancer cells are the most well-defined epigenetic hallmarks in gliomas. [15] Lots of functional TSGs were identified in gliomas including p16 INK4a, p14 ARF, MLH1, O 6 -methylguanine-DNA methyltransferase (MGMT), NDRG2, SLIT2, etc. This review will summarize previously identified candidate epigenetic biomarkers in gliomas based on their biological functions, such as cell cycle, apoptosis, invasion, DNA repair, and pathway related genes [Table 1]. Some representative genes are described in details below. Furthermore, these genes could be potential diagnosis markers and therapeutic targets for gliomas.
Table 1: Summary of TSGs silenced by promoter methylation in glioma


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  Cell Cycle and Proliferation Top


In normal cells, cell cycle and proliferation are controlled by a series of factors. Defects of these have been implicated in cancer initiation and progression. Both p16 INK4a and p14 ARF are alternative splicing isoforms of CDKN2A, located on human chromosome 9p21. [85],[86] As an inhibitor of cyclin-dependent kinase 4 (CDK4) and 6 (CDK6), p16 maintains the unphosphorylated state of tumor suppressor Rb thus inhibiting cell cycle progression. Epigenetic inactivation of p16 by DNA methylation is frequently found in glioma, leading to uncontrollable cell cycle progression, and proliferation in glioma cells. [15],[16],[17],[18] Meanwhile, p14 inhibits MDM2-mediated degradation of p53 protein through inducing conformational changes of MDM2. Epigenetic inactivation of p14 ARF increases the degradation of the p53 protein, which results in the downregulation of p53 induced apoptosis. [21],[22] Methylation of p16 INK[4]a and p14 ARF in gliomas was also reported in many papers. [16],[17],[21],[87]

Besides these well-known cell cycle regulators, other DNA methylated TSGs have the ability to regulate cell cycle and proliferation in gliomas. NSD1 gene encodes a histone methyltransferase involved in chromatin regulation. It contains several functional domains including a SET domain, plant homeodomain, and proline-tryptophan-tryptophan-proline domain. [28] NSD1 function is abrogated in human neuroblastoma and glioma cells by CpG island-promoter hypermethylation. Epigenetic inactivation of NSD1 in transformed cells leads to specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. NSD1 is a functional TSG, which shows tumor suppressor-like features such as reducing colony formation density and inhibiting cellular growth. NSD1 CpG island hypermethylation was frequently detected in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation is a predicting factor of poor outcome in high-risk neuroblastoma. These findings suggest that inactivation of NSD1 leads to a disrupted histone methylation landscape, and it has a translational value as a prognostic marker. [28]

Receptor protein tyrosine phosphatase delta (PTPRD) is a member of the highly conserved family of receptor PTPs. PTPRD gene encodes a transmembrane protein with a cytoplasmic tyrosine phosphatase domain. This gene is frequently silenced via promoter CpG island hypermethylation. Its inactivation occurs in more than 50% of GBM tumors, and this inactivation also predicts poor prognosis in glioma patients. Functional studies suggest that wild-type PTPRD inhibits the growth of GBM and other tumor cells through dephosphorylating oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor silenced during the development of GBMs. [23]

Another cell cycle regulator, Krüppel-like factor 4 (KLF4), is also downregulted in glioma. KLF4 is a member of the KLF zinc-finger-containing transcription factor family. It contains three highly conserved zinc fingers of the C2H2 type along with a transactivating domain at the N-terminus. [88] Loss in physiological KLF4 expression at the RNA and protein levels was found in more than 40% of primary medulloblastomas. Re-expression of KLF4 in D283 medulloblastoma cell line results in significant growth suppression, both in vitro and in vivo. [24] All these data suggests that KLF4 functions as a TSG in the pathogenesis of medulloblastoma.

NDRG2, N-Myc downstream-regulated gene 2, is located at chromosome 14q11.2. The mRNA and protein levels, associated with this gene, were significantly lower in glioma tissues than in adjacent normal tissues. The downregulation of NDRG2, caused by promoter methylation, negatively correlates with the higher glioma grade and poor patient outcome. Overexpression of NDGR2 in human GBM U373 and U138 cells markedly reduced cell proliferation. Studies suggest that NDRG2 can regulate the level of histone acetylation to control glioma cell growth. All these data suggested that NDRG2 plays an important role in GBM carcinogenesis. [25],[26],[89]


  Apoptosis Top


Apoptosis plays a critical role in many normal processes like fetal development and tissue homeostasis. A dysregulation in this process contributes to the development of many diseases, including cancer. [90] Some proapoptotic genes are also silenced by DNA methylation in gliomas. RANK/TNFRSF11A gene encodes a type 1 membrane protein, which binds to its ligand RANKL, activates signaling pathways such as nuclear factor kappa B (NF-kB), JNK, ERK, p38, and AKT/PKB, through phosphorylation of tumor necrosis factor receptor-associated factors protein. [91] Promoter methylation of RANK/TNFRSF11A is frequently detected in GBM tissues and glioma cell lines. Restoration of RANK/TNFRSF11A in GBM cell lines leads to a significant reduction in colony formation and increased apoptosis. This gene regulates apoptosis through NF-kB signaling and other distinct pathways such as cyclic adenosine monophosphate (cAMP)/protein kinase alpha (cAMP response element [CRE]), hypoxia inducible factor, Oct4, and Wnt (T-cell factor/lymphoid enhancer factor) pathway. [37]

Neogenin is a homologue of deleted in colorectal cancer. This gene plays fundamental roles in apoptosis, cellular differentiation, and axon guidance. Studies suggest that Neogenin was frequently downregulated in gliomas by promoter hypermethylation. The downregulation of Neogenin negatively correlates not only with glioma malignancy but also with glioma recurrence. Overexpression of Neogenin elevated apoptotic rate in SHG-44 cells. Studies suggest that Neogenin induces apoptosis and its downregulation, through promoter methylation, is a selective advantage for glioma genesis. [38]

Nonsteroidal antiinflammatory drug-activated gene, NAG-1, is a transforming growth factor-β member. Studies suggest that NAG-1 was frequently methylated in both gliomas and glioma cell lines. NAG-1 basal expression level inversely correlates with tumor grade in glioma. Its expression could be restored by pharmacological demethylation in methylated glioma cells. [39] NAG-1 functions as a tumor suppressor, that acts by inducing apoptosis in glioma cells. PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced GBM cell apoptosis. [40]


  Invasion and Migration Top


The ability of a cancer cell to undergo migration and invasion allows it to change its position from the primary tumor into surrounding tissue. [92] Cell-cell and cell-matrix interactions are crucially involved in metastasis. Disruption of cell adhesion leads to a loss of contact growth inhibition, which is the early step of the neoplastic process. [15] With no lysine (K) 2 (WNK2), a serine/threonine kinase is a member of the WNK protein kinase subfamily. WNK2 is a TSG silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis. Studies found that WNK2 downregulation was associated with increased glioma cell invasion, due to negatively regulated MMP2 expression and activity, through a mechanism involving inactivation of JNK. [49],[50]

Adherens junctional associated protein 1 (AJAP1) is a transmembrane protein found in adhesion junctions and functions to inhibit glioma cell adhesion and migration. AJAP1 may be translocated to the nucleus and regulate gene expression via its interaction with β-catenin complexes. Promoter methylation of AJAP1 is frequently detected in oligodendrogliomas and correlates with low levels of AJAP1 expression. Low AJAP1 gene expression is associated with decreased patient survival rate. [51],[52]

Gliomas invasiveness is also regulated by the interplay between secreted proteases (e.g., cathepsins) and endogenous inhibitors (cystatins). Cystatin E/M (CST6) is a potent inhibitor of cathepsin B, which is frequently overexpressed in gliomas. Research suggests that CST6 is frequently downregulated in glioma samples and this reduced expression correlates with CST6 promoter hypermethylation. Ectopic expression of cystatin E/M in glioma cell lines results in reduced cell motility and invasion. [53],[54]

SLIT2 is a large extracellular matrix-secreted, and membrane-associated glycoprotein. [55] SLIT2/ROBO1 is a conserved ligand-receptor system. Their interactions mediate the repulsive cues on axons and growth cones during neural development. SLIT2 promoter was frequently methylated in glioma cell lines and tumor tissues, which correlates with the downregulated gene expression. The treatment with demethylating agent 5-aza-2'- deoxycytidine in SLIT2 methylated cells will restore SLIT2 gene expression. SLIT2 inhibits glioma migration and invasion by inactivating CDC42-GTP through SLIT2/ROBO1 pathway. [55],[56],[57]


  DNA Repair Top


DNA repair genes could repair spontaneous errors that normally occur at microsatellite sequences during DNA replication. [93] Defects in these DNA repair genes will end up in a particular type of genetic instability. MLH1, a mismatch repair enzyme, is activated in response to DNA damage. Methylation analysis of the CpG sites in MLH1 promoter revealed hypermethylation in recurrent gliomas. This suggests that MLH1 promoter hypermethylation is an early event in the development and progression and the clonal evolution of gliomas. [71]

The product of DNA repair enzyme MGMT gene antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is a frequent event and a key mechanism of MGMT inactivation in GBM patients. Its epigenetic silencing pattern predicts a favorable outcome in patients with GBM who are exposed to alkylating agent chemotherapy. [67],[68],[69],[70]


  RAS Pathway Top


Some pathway related genes are downregulated by DNA methylation in gliomas. The human Ras association domain family 1A (RASSF1A) gene is frequently inactivated by promoter hypermethylation in primary brain tumors and glioma cell lines. RASSF1A was re-expressed in all methylated cell lines after treatment with the demethylating agent 5-aza-2'- deoxycytidine. It could induce apoptosis through MST1 or MOAP-1 proteins. Methylation of promoter CpG islands of RASSF1A may play an important role in the pathogenesis of glioma and medulloblastoma. [75],[76],[94],[95]

Another N-terminal RAS association domain family of genes, RASSF10, was consistently methylated in astrocytic gliomas. Specifically, RASSF10 was constantly methylated in WHO Grades II, and III astrocytomas and WHO Grade IV primary GBMs (67.5%), but unmethylated in Grade I astrocytomas and in DNA from age-matched control brain samples. Pharmacological demethylation by 5-aza-2'- deoxycytidine in methylated glioma cell lines restored RASSF10 expression. In secondary GBMs, RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival, overall survival, and occurred at an early stage in their development. Overexpression of RASSF10 inhibited colony forming ability in two RASSF10-methylated glioma cell lines, and knockdown of RASSF10 increased cell proliferation in U87 glioma cells. [78]


  STAT Pathway Top


JAK/STAT pathway is involved in initiation and progression of several types of cancer. [96],[97] Suppressor of cytokine signaling 3 (SOCS3) is a functional tumor suppressor that inhibits the JAK/STAT signaling pathway. Reports found that SOCS3 promoter hypermethylation was frequently detected in primary GBMs, which was characterized by frequent epidermal growth factor receptor (EGFR) amplification and overexpression. SOCS3-depletion strongly increased tumor cell invasion with no obvious effect on tumor cell proliferation. SOCS3 inactivation by promoter hypermethylation is mutually exclusive to EGFR activation in gliomas and preferentially promotes glioma cell invasion through STAT3 and FAK activation. [72],[74] Hypermethylation of SOCS1 was also reported in gliomas. [72],[73] Reintroduction of SOCS1 into glioma cells sensitizes them to radiation-induced destruction. [73] These genes are critical inhibitors of STAT pathway in gliomas.


  Wnt Pathway Top


Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers including gliomas. [98] A study on hypermethylation investigation of Wnt pathway inhibitors suggested that some Wnt pathway inhibitors are frequently silenced by DNA methylation in gliomas. Hypermethylation of SFRP1, SFRP2, and NKD2 occurred in more than 40% of the primary GBMs, while DKK1 hypermethylation was found in 50% of secondary GBMs. SFRP1−, SFRP5−, DKK1−, DKK3−, NKD1−, and NKD2 expression increased in demethylase drug treatment in their hypermethylated U87-MG GBM cells. [79] Silencing Wnt inhibitors in glioma result in activation of Wnt pathway, leading to neoplastic progression.

LATS2 is a tumor suppressor which inhibits oncogenic Wnt/β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. [99] LATS2 is frequently methylated in astrocytoma, but not in normal brain tissues. The mRNA level of LATS2 in astrocytomas with hypermethylation was significantly lower than those without methylation. LATS2 methylation was detectable in U251 and SHG-44 cell lines, and 5-aza-deoxycytidine restored its expression. [84] The methylation status of LATS2 may provide useful clues to the development of the diagnostic assays for astrocytoma.


  Clinical Application Top


Gliomas are the most common type of primary brain tumor. Around 200,000 patients are diagnosed with a glioma around the world, each year. [100] Even with the available clinical treatments such as surgery, radiotherapy, and chemotherapy the median overall survival is only 14.6 months for GBM patients with a 5-year survival rate in < 5%. [4],[3],[101],[102] Understanding molecular mechanisms in gliomas are critical for the development of new treatment strategies. Identifying useful biomarkers will greatly benefit the early diagnosis of the condition and improve therapeutic treatment in glioma patients. Many methylated TSGs in gliomas have proven that their methylation pattern correlated with poor prognosis in patients [Table 1].

There are three ways for the application usage of aberrant DNA methylation in cancer diagnosis: (1) as a marker to detect cancer cells or cancer derived DNA; (2) as a marker to predict prognosis; and (3) as a biomarker for the assessment of therapeutic response. [103] There are several advantages for promoter methylated biomarkers. Promoter methylation testing in DNA samples provides more stability data than RNA samples. Frequently, DNA samples from cancer cells is only a small fraction of the total DNA in the clinical samples, which are composed of bodily fluids, such as blood, urine, sputum, saliva, and stools. Due to the development in high sensitivity DNA methylation detection technology, epigenetic biomarkers could be easily detected in these samples, even with the small fraction of cancer cell DNA. [103] What is more, the methylation of MGMT and p16 INK4a are already tested and works well in serum samples of glioma patients. [104],[105],[106]

The methylated promoters of TSGs can modulate the sensitivity of GBMs to drugs and radiotherapy. [107] For example, reactivated SOCS1, which is silenced by hypermethylation in glioma, increases the sensitivity of glioma to radiation via inactivation of MAPK. [73] Viral-mediated re-expression of either BEX1 or BEX2 led to increased sensitivity to chemotherapy-induced apoptosis. [45] The methylation status also provides insight for patient specific therapy. The well-known example is MGMT promoter methylation and the resultant response to DNA alkylating agents. The mechanism of DNA alkylating agents is to form cross-links between adjacent stands of DNA, thus inhibit DNA replication to kill cells. The MGMT could directly and specifically remove the cytotoxic alkyl adducts formed at the O 6 position of the guanine by these alkylating agents. The active form of MGMT will inhibit the efficiency alkylating agents. [108] Because MGMT gene is seldom deleted or mutated in cancers, epigenetically silenced MGMT is a predictive biomarker for the response of clinical treatment with radiation and alkylating agents. [107] The predictive value of hypermethylated MGMT promoter is confirmed in several clinical investigations, and MGMT methylation is associated with significantly longer survival in GBMs when treated with radiation and alkylating agents.

In conclusion, both genetic changes and aberrant epigenetic changes contribute to glioma pathogenesis. Epigenetically silenced TSGs fail to suppress the initiation and development of gliomas. The studies on the development of methylated promoters of TSGs as biomarkers, in gliomas, will greatly benefit the diagnosis, prognosis, and therapy of such a devastating malignant tumor. We summarized the recently identified epigenetic silenced TSGs in this review. Continued efforts are needed to investigate TSGs' molecular mechanism, which will expand the knowledge of these markers and lead to the clinical translation of these makers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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