Molecular Epigenetics and Genetics in Neuro-Oncology

Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
Neurotherapeutics (Impact Factor: 5.05). 08/2009; 6(3):436-46. DOI: 10.1016/j.nurt.2009.04.002
Source: PubMed

ABSTRACT Gliomas arise through genetic and epigenetic alterations of normal brain cells, although the exact cell of origin for each glioma subtype is unknown. The alteration-induced changes in gene expression and protein function allow uncontrolled cell division, tumor expansion, and infiltration into surrounding normal brain parenchyma. The genetic and epigenetic alterations are tumor subtype and tumor-grade specific. Particular alterations predict tumor aggressiveness, tumor response to therapy, and patient survival. Genetic alterations include deletion, gain, amplification, mutation, and translocation, which result in oncogene activation and tumor suppressor gene inactivation, or in some instances the alterations may simply be a consequence of tumorigenesis. Epigenetic alterations in brain tumors include CpG island hypermethylation associated with tumor suppressor gene silencing, gene-specific hypomethylation associated with aberrant gene activation, and genome-wide hypomethylation potentially leading to loss of imprinting, chromosomal instability, and cellular hyperproliferation. Other epigenetic alterations, such as changes in the position of histone variants and changes in histone modifications are also likely to be important in the molecular pathology of brain tumors. Given that histone deacetylases are targets for drugs that are already in clinical trial, surprisingly little is known about histone acetylation in primary brain tumors. Although a majority of epigenetic alterations are independent of genetic alterations, there is interaction on specific genes, signaling pathways and within chromosomal domains. Next-generation sequencing technology is now the method of choice for genomic and epigenome profiling, allowing more comprehensive understanding of genetic and epigenetic contributions to tumorigenesis in the brain.

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    • "Therefore, understanding the mechanisms of glioma development and finding new therapeutic options is clinically significant. Glioma development is a multistep process that results from changes in genetic and epigenetic mechanisms [4;5]. Histone methylation is a dynamic process that has been associated with either transcriptional activation or repression [6] and emerging evidence suggests that alterations in histone methylation play a vital role in many neoplastic processes [7]. "
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    ABSTRACT: Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. We examined the role of histone demethylase KDM1 in glioma progression. KDM1 was overexpressed in gliomas and its expression positively correlated with histological malignancy. Knockdown of KDM1 expression or its pharmacological inhibition using pargyline or NCL-1 significantly reduced the proliferation of glioma cells. Inhibition of KDM1 promoted up regulation of the p53 target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 significantly reduced glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9-Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas.
    Oncotarget 11/2012; 4(1). DOI:10.18632/oncotarget.725 · 6.36 Impact Factor
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    • "DNA methylation of CpG islands is an epigenetic modification in higher eukaryotes that affects transcriptional regulation vital for embryonic and neural development (Bogdanovic and Veenstra, 2009). Dysregulation of CpG methylation has been related to genetic instability, cancerogenesis, and neuronal degeneration (Nagarajan and Costello, 2009). On the other hand, epigenetic modifications themselves are sensitive to changes of the cellular redox tone implying a regulatory loop that modulates epigenetic mechanisms of gene expression regulation (Zawia et al., 2009). "
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    ABSTRACT: Embryo development relies on the complex interplay of the basic cellular processes including proliferation, differentiation and apoptotic cell death. Precise regulation of these events is the basis for the establishment of embryonic structures and the organ development. Beginning with fertilization of the oocyte until delivery the developing embryo encounters changing environmental conditions such as varying levels of oxygen, which can give rise to reactive oxygen species (ROS). These challenges are met by the embryo with metabolic adaptations and by an array of antioxidative mechanisms. ROS can be deleterious by modifying biological molecules including lipids, proteins and nucleic acids and may induce abnormal development or even embryonic lethality. On the other hand ROS are vital players of various signaling cascades that affect the balance between cell growth, differentiation and death. An imbalance or dysregulation of these biological processes may generate cells with unrestricted growth and is therefore potentially teratogenic and tumorigenic. Thus, a precise balance between processes generating ROS and those decomposing ROS is critical for normal embryo development. One tier of the cellular protective system against ROS constitutes the family of selenium-dependent glutathione peroxidases (GPx). These enzymes reduce hydroperoxides to the corresponding alcohols at the expense of reduced glutathione. Of special interest within this protein family is the moonlighting enzyme glutathione peroxidase 4 (GPx4) that is a scavenger of lipophilic hydroperoxides on one hand, but on the other hand can be transformed into an enzymatically inactive cellular structural component. GPx4 deficiency – in contrast to all other GPx family members – leads to abnormal embryo development and finally produces a lethal phenotype in mice. This review is aimed at summarizing the current knowledge on GPx isoforms during embryo development and tumor development with an emphasis on GPx4.
    Frontiers in Molecular Neuroscience 07/2011; 4:12. DOI:10.3389/fnmol.2011.00012 · 4.08 Impact Factor
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    • "The hypomethylation is primarily due to the loss of methylation in repetitive elements and other non-transcribed regions of the genome. This genome-wide hypomethylation potentially leads to loss of imprinting, chromosomal instability, cellular hyperproliferation, and activation of oncogenes21 such as K-ras and PU.1.22–25 "
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    ABSTRACT: Prostate cancer is the second most common cancer and the second leading cause of cancer death in men. However, prostate cancer can be effectively treated and cured, if it is diagnosed in its early stages when the tumor is still confined to the prostate. Combined with the digital rectal examination, the PSA test has been widely used to detect prostate cancer. But, the PSA screening method for early detection of prostate cancer is not reliable due to the high prevalence of false positive and false negative results. Epigenetic alterations including hypermethylation of gene promoters are believed to be the early events in neoplastic progression and thus these methylated genes can serve as biomarkers for the detection of cancer from clinical specimens. This review discusses DNA methylation of several gene promoters during prostate carcinogenesis and evaluates the usefulness of monitoring methylated DNA sequences, such as GSTP1, RASSF1A, RARβ2 and galectin-3, for early detection of prostate cancer in tissue biopsies, serum and urine.
    02/2010; 2010(2):17-33. DOI:10.4137/BIC.S3187
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