**1. Introduction**

Cancer has been previously viewed as a disease exclusively driven by genetic changes, including mutations in tumor suppressor genes and oncogenes, and chromosomal abnormalities. However, recent data have demonstrated that the complexity of human carcinogenesis cannot be accounted for by only genetic machineries, but also involves extensive epigenetic abnormalities. The term "epigenetics" refers to the study of heritable changes in gene regulation that do not involve a change in the DNA sequence or the sequence of the proteins associated with DNA (Egger et al. 2004). Epigenetic machineries plays a fundamental role in several biological processes, such as embryogenesis, imprinting, and X chromosome inactivation, and in disease states such as cancer. Several mechanisms were included in the epigenetic machinery, the most studied of which are DNA methylation; histone modifications; and small, noncoding RNAs (Kargul and Laurent 2009; Jeltsch and Fischle 2011). The molecular mechanisms underlie the epigenetic changes in cancer cells are complicate and only began to be elucidated. The best understood component among which is the transcriptional repression of a growing list of tumor suppressor and candidate tumor suppressor genes (Jones and Laird 1999; Esteller 2007). This suppression is associated with abnormal methylation of DNA at certain CpG islands that often lie in the promoter regions of these genes (Esteller 2006, 2007).

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with remarkably distinctive ethnic and geographic distribution among the world. The three major etiologic factors of NPC were well defined as genetic susceptibility, environmental factors and latent infection of the Epstein-Barr Virus (EBV) (Tao and Chan 2007; Lo, To, and Huang 2004). During the passing decade, much attention has been paid to the role of epigenetic alternations occurred in the procedure of tumorigenesis of NPC (Li, Shu, et al. 2011; Tao and Chan 2007).

In this chapter, we will first describe the general mechanisms through which the epigenetic alternations in cancer, then focus on the epigenetic alterations taking place in NPC, with an emphasis on DNA methylation.

Epigenetics of Nasopharyngeal Carcinoma 3

methylation of lysine and arginine residues by histone methyltransferases (HMTs), and the phosphorylation of specific serine groups by histone kinases (HKs). Other histone modifications include attachment of ubiquitination, and sulmolation. Enzymes responsible for the cleavage of some histone modifications, such as histone deacetylases (HDACs), histone phosphatases (PPs), ubiquitin hydrolases (Ubps) and poly (ADPribose)glycohydrolases (PARGs), have already been identified (Biel, Wascholowski, and

Posttranslational modifications are closely related to fundamental cellular events like the activation and repression of transcription. In the case of histone H3, in general, acetylation of H3 at lysine 14 (H3-K14), phosphorylation of serine 10 (H3-S10), and methylation of H3-K4 leads to transcriptional activation. In contrast, the repression of certain genes is linked to deacetylation of H3-K14 and methylation of H3-K9. The specific combination of these modifications has been termed the histone code, that determines histone–DNA and histone–histone contacts, which may in turn regulate the on or off state of genes or unfolding/folding state of the chromatin structure (Jenuwein and Allis 2001; Esteller

Histone modifications and other epigenetic mechanisms such as DNA methylation appear to work together in a coordinated and orderly fashion, to establishing and maintaining gene activity states, thus regulating gene transcription (Fischle, Wang, and Allis 2003; Biel, Wascholowski, and Giannis 2005). In the past decade, more and more attention has been paid on histone modifications, which led to the discovery and characterization of a large number of histone-modifying molecules and protein complexes. Alterations of histonemodifying complexes are believed to disrupt the pattern and levels of histone marks and consequently dysregulate the normal control of chromatin-based cellular processes, ultimately leading to oncogenic transformation and the development of cancer (Esteller

**3.1 Hypermethylation of cellular tumor suppressor genes and the dysregulation of the** 

NPC distinguish itself from other malignancies by the number of genes targeted for silencing by promoter methylation. Several classic tumor suppressor genes, such as p53 and Rb, are found to be mutated in more than 50% of all the tumors, but were rarely found to be mutated in NPC (Burgos 2003; Chang et al. 2002; Tao and Chan 2007). On the contrary, hypermethylation of known or candidate tumor suppressor genes involved in various fundamental pathways has been reported in NPC, such as apoptosis, DNA damage repair, tumor invasion and metastasis. The full list of genes which have been found to be aberrantly

Activated Ras proteins has been shown to play a key role in the development of human cancers (Bos 1989). Ras proteins serve as a node in the transduction of information from a variety of cell surface receptors to an array of intracellular signaling pathways. Mutated variants of Ras (mutations at residues 12, 13 or 61) are found in 30% of all human cancers

Giannis 2005).

2007).

2007).

**Ras signalling** 

**3. NPC as an epigenetic disease** 

methylated in NPC was summarized in table 1.

**corresponding cellular pathways** 
