Is Glioblastoma an Epigenetic Malignancy?

Abstract

Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens.

Hormony tarczycy w ośrodkowym układzie nerwowym (OUN) i ich wpływ na nowotworzenie, zwłaszcza na rozwój i przebieg glioblastoma multiforme — hipoteza badawcza

“…First, functional studies of THRA and THRB in GBM are badly needed. The results of prospective studies on the effect of thyroid hormones on GBM-disturbed epigenetic processes would also be important [11,63,69], as well as studies on the effect of hormones on GBM stem cells [68,70]. The numerous facts presented in this paper were based on studies of GBM samples or cell…”

“…W latach 2010-2015 przedstawiono wiele opartych na wynikach badań doświadczalnych i klinicznych zaburzeń genetycznych, epigenetycznych i ich następstw molekularnych prowadzących do rozwoju GBM i jego zróżnicowanego, skracającego życie ludzkie przebiegu wynikającego z inwazyjności tego glejaka, komórko-wego naciekania i charakterystycznego unaczynienia i oporności na dotychczasowe leczenie [62][63][64][65][66][67]. Zwróco-no również uwagę na rolę niedotlenienia [65], znaczenie komórek mikro-gleju [68,69] i komórek macierzystych nazwanych GBMSCs (glioblastoma stem cells) lub CSCs (cancer stem cells of GBM) [70,71].…”

“…wyniki badań nad wpływem TH na zaburzone w GBM procesy epigenetyczne [11,63,69], czy badanie wpływu hormonów na komórki macierzyste GBM [68,70]. Jednakże w obecnym stanie wiedzy przyjęcie udziału hormonów tarczycy w patogenezie glejaka wielopostaciowego może już mieć wymiar praktyczny.…”

“…Between 2010 and 2015, experimental and clinical studies showed a number of genetic and epigenetic disturbances, leading to the development of GBM and to different but always unfavourable clinical courses in humans [62][63][64][65][66]. It is now generally recognised that in addition to these factors the development and clinical course of GBM, as well as resistance to radiation and pharmacological therapy, depend also on hypoxia, a peculiar role played by micro-glia [68,69], and by the presence of glioblastoma stem cells (GBMSCs) called also cancer stem cells (CSCs) [70,71].…”

Chromatin Memory in the Development of Human Cancers

“…Down regulation of TET function has been observed in human breast, liver, lung, pancreatic and prostate cancers. Despite level variations of 5mC in various cancers, frequent TET mutational inactivation has been reported to associate with decreased 5hmC levels [37][38][39]; therefore, 5hmC has been proposed as a new epigenetic marker for human cancers.…”