Epigenetic Dysregulation in Cancer

Department of Pathology, University of Michigan Medical School, Ann Arbor MI 48109, USA.
American Journal Of Pathology (Impact Factor: 4.59). 09/2009; 175(4):1353-61. DOI: 10.2353/ajpath.2009.081142
Source: PubMed


One of the great paradoxes in cellular differentiation is how cells with identical DNA sequences differentiate into so many different cell types. The mechanisms underlying this process involve epigenetic regulation mediated by alterations in DNA methylation, histone posttranslational modifications, and nucleosome remodeling. It is becoming increasingly clear that disruption of the "epigenome" as a result of alterations in epigenetic regulators is a fundamental mechanism in cancer. This has major implications for the future of both molecular diagnostics as well as cancer chemotherapy.

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Available from: Andrew G Muntean, Oct 04, 2015
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    • "Epigenetic mechanisms (the study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence) are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals [1]. Disruption of such epigenetic processes can lead to altered gene function and malignant cellular transformation [2]. Among epigenetic changes, DNA methylation is a stable but reversible epigenetic modification that regulates gene expression [3]. "
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    ABSTRACT: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are essential compounds in the carbon metabolic cycle that have clinical implications in a broad range of disease conditions. The measurement of the ratio SAM/SAH also called methylation index, has become a way of monitoring the DNA methylation of a cell which is an epigenetic event with important clinical implications in diagnosis; therefore the development of suitable methods to accurately quantify these compounds is mandatory. This work illustrates the comparison of three independent methods for the determination of the methylation index, all of them based on the chromatographic separation of the two species (SAM and SAH) using either ion-pairing reversed phase or cation exchange chromatography. The species detection was conducted using either molecular absorption spectrophotometry (HPLC–UV) or mass spectrometry with electrospray (ESI-MS/MS) as ionization source or inductively coupled plasma (DF-ICP-MS) by monitoring the S-atom contained in both analytes. The analytical performance characteristics of the three methods were critically compared obtaining best features for the combination of reversed phase HPLC with ESI-MS in the MRM mode. In this case, detection limits of about 0.5 ng mL−1 for both targeted analytes permitted the application of the designed strategy to evaluate the effect of cisplatin on the changes of the methylation index among epithelial ovarian cancer cell lines sensitive (A2780) and resistant (A2780CIS) to this drug after exposition to cisplatin.
    Journal of Chromatography A 05/2015; 1393. DOI:10.1016/j.chroma.2015.03.028 · 4.17 Impact Factor
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    • "Given the profound epigenetic divergence that prevails in tumor cells (Akhtar-Zaidi et al., 2012; De Carvalho et al., 2012), it is foreseeable that tumor-specific gene expression response profiles induced by virus infection may be altered by epigenetic modifications and that this could contribute to the heterogeneity of tumor responsiveness to OVs. As discussed previously, epigenetic reprogramming is well known to play an important role in oncogenic transformation and numerous reviews extensively cover the role of epigenetics in cancer (Muntean and Hess, 2009; Baylin and Jones, 2011; Hatziapostolou and Iliopoulos, 2011; Suva et al., 2013). Thus, the remainder of this review aims to highlight current knowledge of genes epigenetically regulated in cancer that are also involved in pathways critical for OV therapy, namely the IFN-mediated antiviral response and antigen presentation (Table 1), and how this contributes to tumor heterogeneity (Figure 1). "
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    ABSTRACT: Oncolytic viruses (OVs) comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.
    Frontiers in Genetics 09/2013; 4:184. DOI:10.3389/fgene.2013.00184
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    • "The gene-silencing pathway mediated by H3K27 methylation is linked to the second major silencing pathway (i.e., DNA methylation) via a deacetylase called SIRT 1 that is recruited by the PRC2 complex and contributes to gene silencing (Muntean and Hess 2009). SIRT 1 levels are increased in the alcohol intragastric tube-feeding rat model cited above. "
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    ABSTRACT: Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.
    Alcohol research : current reviews 03/2013; 35(1):57-67.
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