Special Issue "Epigenetic Therapies and Biomarkers"

Guest Editor
Dr. Gordon Strathdee
Crucible Laboratory, Institute for Ageing and Health, Newcastle University, UK
E-Mail: g.r.strathdee@ncl.ac.uk
Interests: epigenetics; DNA methylation; histone acetylation; Histone methylation; leukaemia; biomarkers; drug resistance

Guest Editor
Dr. Philippe Bertrand
Institut de Chimie des Milieux et Matériaux de Poitiers, Université de Poitiers, CNRS-UMR 6514, 40 Avenue du Recteur Pineau, Poitiers, F-86022, France
E-Mail: philippe.bertrand@univ-poitiers.fr
Interests: chemistry for epigenetic targets; (asymetric) organic synthesis; click chemistry; drug delivery systems; organic functionalization of organic and inorganic materials

Dear Colleagues,

The last 15 years has seen a dramatic increase in our understanding of epigenetics, how epigenetic factors and enzymes regulate gene expression and how this can go awry during the development of disease. Much of this research has focussed on the development of cancer and it is now clear that epigenetic factors are crucial in the development of this disease. This understanding was swiftly followed by a major push to develop novel drugs and to re-examine known drugs for their ability to therapeutically target epigenetic changes. The first epigenetically targeted drugs are already approved for use in patients and many more are currently in clinical trials or pre-clinical development. With our ever increasing understanding of the many genes and pathways required for epigenetic regulation of the human genome the number of potential therapeutic targets for epigenetic therapies continues to rise.

Epigenetic changes also represent a potentially rich source of novel biomarkers, from potential uses in early diagnosis and screening to multiple studies showing links to prognosis or prediction of therapeutic responses. Epigenetic biomarkers are likely to play an important role in the increasing push towards personalised medicine and the rapid advancement in technologies for measuring epigenetic changes should allow increasingly sophisticated combinatorial approaches. Furthermore, there is increasing interest in the role of epigenetic changes as the basis not just for cancer, but for many other common chronic conditions and epigenetic changes associated with these conditions are already being identified. Consequently, it is likely that epigenetic based therapies and biomarkers are going to be of increasing medical importance.

Dr. Gordon Strathdee
Dr. Philippe Bertrand
Guest Editors

Supported Conference
http://epigeneticsymphony.conference.univ-poitiers.fr/

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• Epigenetic
• DNA methylation
• DNMT
• Histone acetylation
• Histone methylation
• HDAC
• 5-azacytidine
• 5-methylcytosine
• Chromatin
• Biomarker

Type of Paper: Review
Title: Phytochemicals and Cancer-Inflammation: Epigenetic Friends or Foe?
Authors: Karen Heyninck ², Katarzyna Szarc vel Szic ¹, Ajay Palagani ^1,2, Linde Sabbe ², Behrouz Hassania ², Guy Haegeman ² and Wim Vanden Berghe ^1,2
Affiliations: ¹ Laboratory of  Protein Science, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, Belgium
² Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L.Ledeganckstraat 35, Gent, Belgium
Abstract: Cancer, as one of the non-communicable diseases, remains one of the leading causes of death around the world. Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. On the other hand, numerous clinical, epidemiological and laboratory studies have highlighted the importance of nutritional anti-inflammatory compounds as chemopreventive agents in those complex human diseases. Many clinical trials are ongoing on the use of specific nutritional supplements and personalized diet to prevent or attenuate cancer. Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of key inflammatory genes and noncoding RNAs, recently emerged as major governing factors in cancer initiation, promotion, metastasis and modulation of cancer drug sensitivity.  Epigenetic defects (epimutations) are thought to be more easily reversible (when compared with genetic defects) and, as such, have inspired efforts to identify novel compounds that correct epimutations or prevent disease progression. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies.  This has recently launched reexploration of chemopreventive phytochemicals to identify compound specific epigenetic effects which allow (re)programming of cancer stem cells,  prevent metastasis or sensitize for drug sensitivity.  As such, botanicals may correct or prevent carcinogenic epigenetic marks in the body and the host immune system, and protect against aggressive cancer malignancies. Many bioactive phytochemicals produced by environmentaly stressed plants modulate key regulators of mammalian physiology in ways that are beneficial to health by priming a cellular stress response. This review will provide an overview of stress adaptive epigenetic effects of chemopreventive phytochemicals on global DNA methylation, specific promoter methylation of silenced tumor suppressor genes, histone modifications, and miRNAs deregulated during metastatic cancer or cancer drug resistance. Furthermore, we will discuss its potential impact on inflammatory pathways mediated by nuclear receptors and transcription factors such as NFB, Nrf2, AP1, or Stat3,  involved in tumor development, cancer therapy and prevention.

Type of Paper: Review
Title: DNA Methylation as a Biomarker in Leukaemia
Authors: Hannah E. Gautrey and Gordon Strathdee
Affiliation: Crucible Laboratories, Institute for Ageing and Health, Newcastle University, UK
Abstract: Molecular markers are increasingly used to help direct patient treatment in leukaemia, as well as other cancer types. While markers such as specific cytogenetic changes or gene mutations have proved very valuable, further sources of additional molecular markers are urgently needed if the ultimate aim of personalised cancer treatment is to be achieved. Alterations in DNA methylation are among the most attractive sources of new prognostic markers. Altered patterns of DNA methylation are one of the hallmarks of cancer, including both genome wide hypomethylation in association with local increases in methylation targeted at gene associated CpG islands. Increased methylation, or hypermethylation, of gene associated CpG islands appears to be of particular importance. This is now clearly established as a crucial mechanism leading to the inactivation of tumour suppressor genes and individual tumours have been reported to exhibit greater than 1000 hypermethylated CpG islands. This extreme prevalence, in association with recently developed techniques which have greatly enhanced the ease of detection of DNA methylation changes has lead to increasing interest in their potential as novel prognostic markers. This review will discuss some of the promising methylation based markers already identified, future directions likely to lead to the identification of new markers or novel marker combinations, as well as what will be required to take these observation out of the lab and into the clinic where they can improve patient treatment.

Type of Paper: Article
Title: Problems and Pitfalls in Interpreting FOXP3 TSDR Demethylation"
Author: Wayne W. Hancock
Affiliation: Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; E-Mail: whancock@mail.med.upenn.edu
Abstract: The epigenetic status of FOXP3, the key transcription factor of CD4+CD25+ FOXP3+ T-regulatory (Treg) cells, has a central role in Treg biology. Demethylation of the Treg-specific demethylated region (TSDR) within the FOXP3 intronic site was reported to be a specific marker of stable and functionally-competent thymic-derived natural Tregs, allowing their discrimination from activated CD4+CD25+FOXP3+ effector T cells and in vitro induced Tregs. Assessment of TSDR demethylation in PBMC and other clinical samples was also suggested as a practical, sensitive and highly specific method to calculate the number of "true Tregs". There is also a second important demethylated region, located in an upstream FOXP3 enhancer site, that was reported to be fully demethylated in Tregs but not in Teff cells, which may also be of clinical utility in identifying Treg cells. However, the data regarding FOXP3 demethylation were largely derived using resting cells in non-inflammatory conditions. In the current work we showed that demethylation in FOXP3 in both regions is an active and dynamic process, sensitive to cell activation and exposure to cytokines such as IL-2. We evaluated Treg numbers in healthy donors, and in kidney or liver transplant recipients, and showed that TSDR demethylation is important for Treg suppressive function, but cannot be used to calculate their number in PBMC samples. Our data extend knowledge of the epigenetic regulation of FOXP3, and also identify important limitations to its diagnostic and/or prognostic significance when using unfractionated cells.