oncology reports

ONCOLOGY REPORTS 31: 523-532, 2014

Epigenetic regulation and cancer (Review)

Q.W. CHEN1, X.Y. ZHU1, Y.Y. LI2 and Z.Q. MENG1

1

Department of Integrated Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032; 2Department of Biochemistry and

Molecular Biology, Peking University Health Science Center, Beijing 100191, P.R. China

Received August 7, 2013; Accepted September 4, 2013

DOI: 10.3892/or.2013.2913

Abstract. ‘Epigenetics’ is defined as the inheritable changes in gene expression with no alterations in DNA sequences. Epigenetics is a rapidly expanding field, and the study of epigenetic regulation in cancer is emerging. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs have been proven to prolong survival and to be less toxic than conventional chemotherapy. Promising results from combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In the present review, examples of studies that demonstrate the role of epigenetic regulation in human cancers with the focus on histone modifications and DNA methylation, and the recent clinical and translational data in the epigenetics field that have potential in cancer therapy are discussed. Contents1. 2. 3. 4. 5. 6.

Epigenetic mechanismsDNA methylationHistone modificationmicroRNAs

Epigenetic abnormalities in tumorigenesis anddevelopment

Epigenetic therapy and future challenges

1. Epigenetic mechanisms

In the eukaryotic nucleus, DNA is compacted into a chromatin structure with the nucleosome as the basic unit, in which histone octamer is surrounded by the 147 bases of DNA for 1.7 laps. The histone octamer includes two elements of the core histone (H3, H4, H2A and H2B) (1). The packaging of DNA into chromatin presents a potential barrier to factors that require DNA as their template. There are mainly three modifications regulating chromatin structure and epigenetic mechanisms of gene expression, including DNA methylation, histone covalent modification and microRNAs (miRNAs) (2). These modifications jointly constitute the ‘Epigenetic code’ to modulate the expression of the mammalian genome in different cell types, through developmental stages and in diverse disease states including cancer (2-4).2. DNA methylation

DNA methylation is a widespread modification in bacteria, plants and mammals, and this covalent molecular transfor-mation is a natural modification of DNA. DNA methylation which is produced during DNA replication is considered as a stable gene-silencing mechanism. In eukaryotic cells, DNA methylation is the covalent modification taking place at the 5' end of the CpG dinucleotide of the cytosine ring and with S-adenosyl-methionine as its methyl donor. This reaction is catalyzed by the DNMT family, including DNMT1, DNMT3A and DNMT3B. During the process of embryo formation, DNMT3A and DNMT3B are required for DNA methylation from scratch, while DNMT1 is considered to be the methyl-transferase maintaining the methylation status (5).

This covalent modification can inhibit the activity of gene transcription; either by blocking the combination of a tran-scription factor and its binding sites (6), or through recruitment of methylated binding domain proteins that mediate inhibition of gene expression (7). In mammalian cells, DNA methylation occurs mainly in CpG dinucleotides (8). However, CpG sites are not randomly distributed in the genome, but are concentrated in short CpG-rich DNA fragments or DNA fragments in the long repeat so-called ‘CpG islands’ (8,9). Although for normal cells, the majority of CpG sites of the genome are methylated, usually the cytosine in CpG islands is not methylated in the development and differentiation of tissues. However, in normal cells, certain subsets of CpG islands at the promoter can be

Correspondence to: Professor Z.Q. Meng, Department of Integrated

Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China

E-mail: mengzhq@gmail.com

Key words: epigenetics, DNA methylation, histone modification,

microRNAs, cancer

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