Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Lee, Eun Joon; Rath, Peter; Liu, Jimei; Ryu, Dungsung; Pei, Lirong; Noonepalle, Satish; Shull, Austin Y.; Qi, Feng; Litofsky, N. Scott; Miller, Douglas C.; Anthony, Douglas C.; Kirk, Mark D.; Laterra, John; Deng, Libin; Xiao, Hong; Wang, Xinguo; Choi, Jeong Hyeon; Shi, Huidong

doi:10.1016/j.jgg.2015.06.003

Cited by 50 publications

(47 citation statements)

References 59 publications

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“…PTPRN2 has been reported to be significant hypermethylated in squamous cell lung cancer and glioblastoma [20, 29]. PTPRN2 resulted in the top list of marker down methylated in HCC, as reported by Shen et al [10], and similarly to our results the hypomethylation of this gene was restricted to the gene body region.…”

Section: Discussionsupporting

confidence: 91%

“…These epimutations were characterized by hypermethylation at promoters level and concomitant hypomethylation at gene body level in HCC tumor tissues (Table 3). Interestingly, a similar epigenetic signature for AJAP1, ADARB2 and PTPRN2 has been previously reported in glioblastoma [20–21]. Unfortunately, it was not possible using microarray-based method to understand if these epigenetic alterations were allele-specific.…”

Section: Discussionmentioning

confidence: 66%

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Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

et al. 2017

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Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC.HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC.In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

et al. 2017

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“…Subsequently, it was reported that the hypermethylation of the SPINT2 promoter region underpins reduced HAI‐2/SPINT2 expression in the U87 human glioblastoma cell line . Furthermore, methylation of the SPINT2 gene was also reported in glioblastoma‐derived cancer stem cells . Medulloblastoma, another highly malignant CNS tumor, also shows hypermethylation and silencing of the SPINT2 gene .…”

Section: Introductionmentioning

confidence: 90%

Aberrant methylation and silencing of the SPINT2 gene in high‐grade gliomas

et al. 2018

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Hepatocyte growth factor activator inhibitor type 2 (HAI‐2), encoded by the SPINT2 gene, is a membrane‐anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor (HGF), a ligand of MET receptor. Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma‐derived cancer stem cells. However, the incidence of SPINT2 methylation in tumor tissues obtained from glioma patients is unknown. In this study, we analyzed the methylation status of the SPINT2 gene of eight human glioblastoma cell lines and surgically resected glioma tissues of different grades (II, III, and IV) by bisulfite sequence analysis and methylation‐specific PCR. Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2 mRNA compared to cultured astrocytes and normal brain tissues. However, all glioblastoma lines expressed mRNA for HGF activator (HGFAC), a target protease of HAI‐2/SPINT2. Forced expression of SPINT2 reduced MET phosphorylation of U87 glioblastoma cells both in vitro and in intracranial xenografts in nude mice. Methylation‐specific PCR analysis of the resected glioma tissues indicated notable methylation of the SPINT2 gene in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, III, and IV gliomas, respectively. Analysis of RNA sequencing data in a public database indicated an increased HGFAC/SPINT2 expression ratio in high‐grade compared to low‐grade gliomas (P = .01). In summary, aberrant methylation of the SPINT2 gene is frequently observed in high‐grade gliomas and might confer MET signaling in the glioma cells.

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“…These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors, indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate TSGs that are frequently downregulated in GBMs, such as SPINT2, NEFM, and PENK (42).…”

Section: Dna Methylationmentioning

confidence: 99%

Cancer Stem-Like Cells in Glioblastoma

Cheray¹,

Begaud²,

Deluche³

et al. 2017

Glioblastoma

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Glioblastoma is currently described as the worst brain tumor because of its aggressiveness and poor prognosis. Chemotherapy and irradiation are not curative, and the average survival for patients with glioblastoma is around 15 months. The cellular heterogeneity and infiltrative capability of glioblastoma make complete surgical resection almost impossible. Moreover, the presence of cancer stem-like cells in this tumor leads to therapeutic resistance and tumor recurrence after surgery. Numerous studies have explored the physiology of these cancer stem cells, and attempts have been made to develop devices aimed at isolating this rare population of cells. This chapter describes the complexity of cancer stem cells in glioblastoma. Their role in autophagy, gene regulation by epigenetic modifications, and the challenges in isolating these cells are addressed. This knowledge may pave the way for a better understanding of cancer stem cells in glioblastoma, and the potential development of new therapeutic strategies for this deadly disease.

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Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Cited by 50 publications

References 59 publications

Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

Aberrant methylation and silencing of the SPINT2 gene in high‐grade gliomas

Cancer Stem-Like Cells in Glioblastoma

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