Oncogene (2010) 29, 1405–1420 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Viral epigenomes in human tumorigenesis AF Fernandez1 and M Esteller1,2 1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain and 2Institucio Catalana de Recerca i Estudis Avanc¸ats (ICREA), Barcelona, Catalonia, Spain Viruses are associated with 15–20% of human cancers is altered in cancer (Fraga and Esteller, 2005; Chuang worldwide. In the last century, many studies were directed and Jones, 2007; Lujambio et al., 2007). towards elucidating the molecular mechanisms and genetic DNA methylation mainly occurs on cytosines that alterations by which viruses cause cancer. The importance precede guanines to yield 5-methylcytosine; these of epigenetics in the regulation of gene expression has dinucleotide sites are usually referred to as CpGs prompted the investigation of virus and host interactions (Herman and Baylin, 2003). CpGs are asymmetrically not only at the genetic level but also at the epigenetic level. distributed into CpG-poor regions and dense regions In this study, we summarize the published epigenetic called ‘CpG islands’, which are located in the promoter information relating to the genomes of viruses directly or regions of approximately half of all genes. These CpG indirectly associated with the establishment of tumori- islands are usually unmethylated in normal cells, with genic processes. We also review aspects such as viral the exceptions listed below, whereas the sporadic CpG replication and latency associated with epigenetic changes sites in the rest of the genome are generally methylated and summarize what is known about epigenetic alterations (Jones and Takai, 2001). in host genomes and the implications of these for the DNA methylation is a normal cellular process in tumoral process. The advances made in characterizing mammalian cells that enables the normal expression epigenetic features in cancer-causing viruses have im- pattern to be maintained; it is involved in genomic proved our understanding of their functional mechanisms. imprinting (Feinberg et al., 2002), X-chromosome in- Knowledge of the epigenetic changes that occur in the activation in females (Payer and Lee, 2008) and silencing genome of these viruses should provide us with markers for parasitic and foreign elements (Doerfler, 1991), among following cancer progression, as well as new tools for other processes. However, methylation of CpG islands in cancer therapy. promoter regions is often associated with gene silencing, Oncogene (2010) 29, 1405–1420; doi:10.1038/onc.2009.517; and aberrant DNA methylation occurs in most cancers, published online 25 January 2010 leading to the silencing of some tumor-suppressor genes (Jones and Baylin, 2002; Esteller, 2008). Keywords: epigenetics; DNA methylation; histone modi- fication; virus; viral oncogenes; human cancer Viruses and cancer Since 1898, when Martinus Beijerinck discovered the Epigenetics first known virus, the tobacco mosaic virus, 45000 types of viruses have been described in detail (Breitbart Since 1987, when Robin Holliday defined epigenetics as and Rohwer, 2005). Peyton Rous discovered the first heritable changes in gene expression that are not due known tumorigenic virus in birds in 1911 and, more to any alteration in the DNA sequence (Holliday, 1987), recently, in 1964, Michael Anthony Epstein and Yvonne much has been discovered in this field. We now know Barr first discovered a virus known to be involved in that epigenetics, which includes the methylation status human cancer (the Epstein–Barr virus, EBV). We now of DNA and the posttranslational modifications of know that viruses infect all types of cells and cause a histones, has an important function in tumorigenesis in variety of human diseases, from the common cold to mammals (Jones and Baylin, 2002; Esteller, 2008). The AIDS and cancer. best-known epigenetic marker is DNA methylation, and Viruses produce disease by different routes, depend- together with specific histone modifications and specific ing on the viral species and the specific organ or miRNA signatures, it defines a molecular landscape that organism they affect. Viral infection can lead to asymptomatic effects, acute clinical disease, neurological disorders and induction of various cancer types. The Correspondence: Dr M Esteller, Cancer Epigenetics and Biology interactions between a virus and its host can produce Program (PEBC), 3rd Floor, Hospital Duran i Reynals, L’Hospitalet, different consequences, from no apparent change in Gran Via 199-203, 08907 Barcelona, Catalonia, Spain. E-mail: [email protected] the infected cell to the death of the host cell arising Received 31 July 2009; revised 7 September 2009; accepted 18 December from alterations of the cell membrane and apoptosis 2009; published online 25 January 2010 (Roulston et al., 1999). Some viruses can persist over Viral epigenomes in human tumorigenesis AF Fernandez and M Esteller 1406 time, despite active immunity, and cause no apparent response. However, viruses are not sufficient for carcino- changes to the infected cell. This latency is a character- genesis, and additional factors, including host immunity istic of the herpes virus group, some members of which, and cell mutations, are necessary for a tumoral process to such as the herpes simplex virus, can induce cell be initiated (McLaughlin-Drubin and Munger, 2008). proliferation without causing malignancy (Barozzi Viruses that establish latent infections need to avoid et al., 2007), or of the human papilloma virus (HPV) recognition by the immune system, as this would group, several members of which can unleash cancer otherwise eliminate the infection. Different viral evasion (zur Hausen, 2009). strategies have been identified, but all of them are The proportion of cancers caused by infectious essentially aimed at camouflaging the virus in the host agents, including bacteria, parasitic worms and viruses, cell, restricting the expression of viral genes and proteins was recently estimated to be 420% (Bouvard et al., that are indispensable for viral persistency, and avoiding 2009). The contribution of several viruses is especially the expression of genes associated with immune high in certain cancer types. For instance, human response. Viral DNA methylation could be the masking hepatitis B virus (HBV) and human hepatitis C virus mechanism by which many viruses are able to achieve (HCV) are associated with 80% of hepatocellular this (Fernandez et al., 2009). carcinomas (HCCs), EBV is associated with 30% of DNA methylation is responsible, through the silen- Hodgkin’s lymphomas and HPV is positive in 495% of cing of repetitive genomic sequences, for the inactivation cervical carcinomas (zur Hausen, 2006). Many of the of integrated foreign DNA, that is, retrotransposons products from these oncogenic viruses (oncoviruses) such as L1 and ALU elements, proviral sequences from carry out functions that disrupt cell processes, such endogenous retroviruses and other transposable ele- as apoptosis and cell-cycle checkpoint activation ments. (Yoder et al., 1997; Colot and Rossignol, 1999). (McLaughlin-Drubin and Munger, 2008). Although In this regard, it has been proposed that DNA oncoviruses from different virus families use diverse methylation may have arisen as a genome-defense strategies that contribute to cancer development, they system to prevent chromosomal instability, transloca- share many common features, among which the inter- tions and gene disruption caused by the reactivation of actions with cellular targets such as p53 and Rb (Javier these transposable DNA sequences (Yoder et al., 1997; and Butel, 2008; McLaughlin-Drubin and Munger, Rollins et al., 2006). In addition, eukaryotic cells have 2008) are of particular note. developed several defense mechanisms against the Known and potential human tumor viruses belong to a uptake, integration and continued expression of foreign number of families, either DNA viruses or RNA viruses DNA (such as viruses) in which gene-specific sequence that retrotranscribe their genome to DNA. General methylation has an important role (Doerfler, 1991). This information about these viruses with known and potential de novo methylation of foreign genes in eukaryotic associations with human cancer is provided in Table 1. genomes can be viewed as an ancient cell defense Oncoviruses tend to cause persistent infections because mechanism against the intrusion of foreign genetic they have developed strategies for evading the host immune material (Doerfler, 1991, 1996). Table 1 General information about the viruses associated with human cancer Virus Genome Viral taxonomy Size Viral oncoprotein Human cancers DNA methylome EBV dsDNA Herpesviridae 171.823 nt LMP1, BZLF1, EBNA2, BL, NPC, HD, GC Partially (all TSS) EBNA3, BRLF1 KSHV dsDNA Herpesviridae 137.969 nt LANA, vIRFs KS, PEL, MCD Partially HPV dsDNA Papillomaviridae B8.000 nt E2, E6, E7 Cervical, oropharynx, Complete anogenital, skin HBV dsDNA (partial) Hepadnaviridae 3.215 nt HBx HCC Complete HCV ssRNA Flaviviridae 9.646 nt NS4B? HCC None HTLV-I ssRNA4dsDNA Retroviridae 8.507 nt Tax ATL Partially (LTR regions, TSS) HIV ssRNA4dsDNA Retroviridae 9.181 nt Unknown Unknown Partially (LTR regions) HCMV dsDNA Herpesviridae 230.290 nt IE1-72?, IE2-86? CRC, glioma, prostate Partially (not in humans) SV40 dsDNA Polyomaviridae 5.243 nt T-Ag Osteosarcoma, mesothelioma, brain None JCV dsDNA Polyomaviridae