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Epigenetic Abnormalities in Brain Tumors
Başlık:
Epigenetic Abnormalities in Brain Tumors
Yazar:
Chen, Xiaoyue, author.
ISBN:
9780438117693
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (125 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Zhiguo Zhang; Jann N. Sarkaria Committee members: Daniel D. Billadeau; Robert B. Jenkins; Jan van Deursen.
Özet:
Epigenetics is the study of heritable changes that alters gene expression without changing DNA sequence. Previous studies showed that epigenetic alterations were associated with tumor initiation, progression and the development of chemo-resistance in cancers. Recently, several key epigenetic alterations were found in brain tumors. One key epigenetic regulation in adult glioblastoma is O6-methylguanine DNA methyltransferase (MGMT) promoter hypermethylation. Hypermethylated MGMT promoter is associated with reduced MGMT expression, better response to Temozolomide (TMZ) treatment and longer overall survival in glioblastoma patients. In pediatric patients, H3F3A K27M mutation, which abolishes the crucial lysine residue for post-translational modification on histone, leads to a great reduction in H3K27me3 in a dominant negative manner and initiates the pathogenesis of pediatric brainstem gliomas. Despite the importance of epigenetic mechanisms in brain tumors, therapies targeting epigenetic alterations are not clinically available. Therefore, in order to develop novel epigenetic therapies, a more complete understanding of epigenetic regulators in brain tumor development is essential. In this thesis, the role of epigenetic alterations in glioblastoma and diffuse intrinsic pontine glioma is summarized in Chapter I, the role of epigenetic alterations in acquired TMZ resistance is discussed in Chapter II, the efficacy of an epigenetic therapy in diffuse intrinsic pontine glioma (DIPG) is tested in Chapter III.
MGMT promoter methylation is one of the most important glioblastoma biomarkers. Hypermethylation of this promoter is associated with a lower MGMT expression and a higher efficacy of TMZ therapy. However, MGMT promoter methylation state does not entirely correlate with TMZ sensitivity in patients. Discrepancies between MGMT promoter methylation status and MGMT gene expression have been widely reported. In Chapter II, I show that, due to alterations on histone modifications, the activity of a novel enhancer is upregulated during the development of TMZ resistance. Activating this novel enhancer drives MGMT expression and TMZ resistance, while deleting this enhancer sensitizes cells to TMZ. This observation indicates that, in addition to promoter methylation status, MGMT expression is also regulated by enhancer activity. Our model helps explain the previous discrepancies between MGMT promoter methylation status and protein expression level.
Besides the development of resistance, epigenetic alterations play an important role in the initiation of DIPG. However, whether epigenetic alterations can be targeted to treat DIPG is unknown. In Chapter III, I show that inhibiting histone demethylase activity can restore the H3K27me3 in H3F3A K27M mutant DIPG cells. This result demonstrates that increasing H3K27me3 may be a valid therapeutic strategy for treating K27M-expressing DIPG patients.
Notlar:
School code: 1542
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(695406.1) | 695406-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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