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Post-Translational Histone Modifications in Circulating Nucleosomes As New Biomarkers in Colorectal Cancer

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Post-Translational Histone Modifications in Circulating Nucleosomes As New Biomarkers in Colorectal Cancer in vivo 28: 287-292 (2014) Review Post-translational Histone Modifications in Circulating Nucleosomes as New Biomarkers in Colorectal Cancer UGUR GEZER1 and STEFAN HOLDENRIEDER2 1Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey; 2Institute of Clinical Chemistry and Pharmacology, University Hospital Bonn, Bonn, Germany Abstract. Although many potential biomarkers for improved the survival rates of patients with CRC (2). Overall colorectal cancer (CRC) have been detected, rarely do they 5-year survival rates for disease localized to the colon (stage I- have usage in clinical practice. New biomarkers are needed II) is high (about 80%) but decreases with spread of the to detect CRC at an early phase, to detect recurrence and disease to regional lymph nodes (about 60%) or distant organs monitor therapeutic response. It has become increasingly (only 8%) (3). Metastasis occurs most commonly to the liver evident that altered epigenetic control of gene expression (4). The majority of patients are diagnosed with stage III or plays an important role in carcinogenesis. In addition to IV disease for whom several chemotherapy regimens are DNA methylation and non-coding RNAs, post-translational available, while advances in molecular diagnostics have histone modifications play an important role in gene allowed the development of targeted therapeutic agents (e.g. regulation and carcinogenesis. Knowledge regarding the inhibitors of vascular endothelial growth factor or its patterns of histone modifications in CRC is accumulating. receptors) to reduce the risk of metastasis or to treat it. Additionally, histone modification alterations can be detected At the molecular level, CRC is a heterogeneous disease and in nucleosomes circulating in the blood of patients with this heterogeneity is associated with differences in disease cancer offering the possibility to use them as biomarkers in progression, survival and response to chemotherapeutic agents CRC and other types of cancer. In the present review, we (5). Three molecular pathways, chromosomal instability, discuss the potential clinical utility of histone modifications microsatellite instability and CpG island methylator in circulating nucleosomes for the diagnosis and estimation phenotype, have been proposed to contribute to colorectal of prognosis in patients with CRC. carcinogenesis. The initiation of cancer through these mechanisms is followed by pathways with distinct clinical, The Need for Biomarkers for Colorectal Cancer pathological, and genetic characteristics. Recent data have (CRC) Detection demonstrated that several genetic and epigenetic changes are important in determining patient prognosis and survival (6). Despite intensive research, CRC represents a serious public Despite advancements in treatment options, improvements health issue as it is still one of the leading types of cancer with in patient survival for CRC have been limited due to lack of respective to incidence and mortality (1). Over the past two early detection (7). Even if many potential biomarkers have decades, advances in screening programs, surgical techniques, been detected, the number of biomarkers that have been adjuvant chemotherapy and surveillance programs have incorporated into clinical practice is surprisingly small (8). Biomarkers to improve CRC diagnosis, prognosis and prediction of treatment response, therefore, represent opportunities to improve patient outcome. Carcinoembryonic This article is freely accessible online. antigen (CEA) is the most widely used tumor marker for CRC in clinical practice, with its main utility in indicating Correspondence to: Stefan Holdenrieder, MD, Institute of Clinical disease recurrence in the liver. Tumor biomarkers identified Chemistry and Clinical Pharmacology, University Hospital Bonn, in CRC tissues have been used to guide chemotherapy Sigmund-Freud Str. 15, 53127 Bonn, Germany. Tel: +49 22828712126, regimens and include the kirsten rat sarcoma viral oncogene Fax: +49 22828712159, e-mail: [email protected] homolog (KRAS), v-raf murine sarcoma viral oncogene Key Words: Circulating nucleosomes, epigenetic alterations, histone homolog B (BRAF), microstallite instability (MSI) and sma modifications, serum, colorectal cancer, review. and dad releated family member 4 (SMAD4) (8). Reliable 0258-851X/2014 $2.00+.40 287 in vivo 28: 287-292 (2014) biomarkers are needed to detect CRC in an early phase, to tails is dynamic and achieved by a number of different guide treatment, as well as for surveillance to detect histone-modifying enzymes. These include histone recurrence and monitor therapeutic response. acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), histone demethylases Cancer Epigenetics (HDMs), histone ubiquitinating enzymes as well as de- ubiquitinating enzymes. They can be either specific (i.e. Traditionally, cancer development has been attributed to HMTs and HDMs) or general (i.e. HATs and HDACs) in purely genetic mechanisms, however, accumulating evidence their ability to recognize and alter the amino acid residues of suggests that much of its complexity can be directly histone tails (16, 17) (Figure 1). attributed to epigenetics (9). The term epigenetics is defined Nearly a dozen different histone modifications have been as the study of inherited phenotypes which are not encoded detected which can modify more than 150 conserved residues by the DNA sequence (10) and commonly refers to changes within histone proteins (18). Post-translational modifications in DNA methylation, microRNAs, histone modifications, and of histones can regulate the accessibility of chromatin. other chromatin elements that can alter gene expression. Generally, acetylation and phosphorylation are thought to Together these form the epigenome and regulate the high change chromatin structure by altering the net positive charge complexity of the mammalian genome, providing the basis of the histone proteins, thereby rendering DNA sequence of differentiation, development and cellular homeostasis. information more accessible (19). Acetylation of histone tails These mechanisms are interrelated and stably maintained is typically associated with transcriptional activation of genes, during cell divisions and enable the cell to react and adapt while the functional consequences of methylation depend to altered environmental conditions (11). mainly on the number of methyl groups and their location It has become increasingly evident that altered epigenetic within the histone tail (20). Examples for modifications that control of gene expression plays an important role in are associated with open chromatin and active gene expression carcinogenesis (12). Many epigenetic changes, such as include histone 3 lysine 4 di- and trimethylation (H3K4me2 hypomethylation of oncogenes, hypermethylation of tumor- and H3K4me3, respectively) and histone 3 lysine 9 suppressor genes, depletion of hydroxymethylation, changes monomethylation (H3K9me1). Histone 3 lysine 27 di- and of histone acetylation and methylation patterns, and trimethylation (H3K27me2 and H3K27me3, respectively) and variations in microRNA expression level, are known to be histone 3 lysine 9 di- and trimethylation (H3K9me2 and associated with many types of cancers (13). With the H3K9me3, respectively) are associated with inactive advancement of new technologies, it becomes clear that chromatin and repression of gene expression (21). altered epigenetic patterns occur in different types of cancer The high combinatorial potential of different modifications (11). In the 1990s, DNA methylation was the main focus of has been described as the ‘histone code’ (20, 22) and a epigenetic cancer studies (14). However, during the past multitude of different post-translational modifications play an decade, this focus has been broadened by research into the important role in eukaryotic gene regulation and in fine- role of covalent chromatin modifications in gene regulation, folding of nucleosomes into higher-order chromatin (23). carcinogenesis, and cancer prognosis (15). In the present Distinct modifications at specific histone tail residues serve as review, we discuss the potential utility of histone domains for interaction with specific proteins, and such modifications in CRC and their detection in blood interactions compartmentalize chromatin into heterochromatin circulation. and euchromatin as illustrated by recent genome-wide chromatin modification mapping studies (24). Distinct histone Post-translational Modifications of Histones modifications correlate with distinct genomic regions; for example, H3K4me3 with promoters; H3K39me1 with The coiling of DNA around core histone proteins (H2A, enhancers; H3K9 and H3K27 acetylation (H3K9ac, H3K27ac) H2B, H3 and H4) forms nucleosomes that are the basic units with active regulatory regions; H3K36me3, H3K79me2 and of eucaryotic chromatin packaging. The core histones display H4K20me1 with transcribed regions and intron/exon usage; highly dynamic N-terminal amino acid tails of 20-35 residues H3K27me3 with polycomb-repressed regions; and H3K9me3 in length extending from the surface of nucleosome. Given with pericentromeric heterochromatin (24, 25). that histone residues on these tails can become post- As histone modifications play fundamental roles in gene translationally methylated, phosphorylated, acetylated, regulation and expression, it is not surprising that aberrant sumolyated, ubiquitinated, and ADP-ribosylated. Lysine patterns
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