Viral manipulation of the host epigenome for oncogenic transformation

Abstract

The cancerous cellular state is associated with multiple epigenetic alterations, but elucidating the precise order of such alterations during tumorigenic progression and their contributions to the transformed phenotype remains a significant challenge in cancer biology. Here we discuss recent findings on how viral oncoproteins exploit specific epigenetic processes to coerce normal cells to replicate when they should remain quiescent - a hallmark of cancer. These findings may highlight roles of epigenetic processes in normal biology and shed light on epigenetic events occurring along the path of non-viral neoplastic transformation.

Figure 1. Schematic structure of small e1a and its interactions with cellular proteins required for induction of cell cycling

Small e1a posses three conserved regions (CRs), CR1, CR2 and CR4, and lacks CR3, which is present in large E1A. The CR1 region and conserved residues in the N terminus are required for interaction with the lysine acetyltransferase p300 or its closely related paralogue CBP. CR2 and residues in CR1 bind to the tumour suppressor retinoblastoma (RB) protein family.

Figure 2. A model for e1a-induced epigenetic reprogramming in primary human fibroblasts

Three classes of gene capture the main trends in global gene expression changes induced by small e1a. Small e1a associates transiently with the cellular antiviral response gene promoters through its interaction with the lysine acetyltransferase p300 (or its closely related paralogue CBP) early after infection (6 h); p300/CBP remains associated with these genes at 24 h post-infection at which time point it may have a repressive function. By 24 h, and maybe earlier, the tumour suppressor proteins retinoblastoma (RB) and p130 also associate with these genes, which show an increased density of histones and his-tone H4 lysine 16 acetylation (H4K16ac), low H3K18ac and H3K9ac levels, and are repressed. Small e1a also binds transiently to growth and cell cycle genes through interactions with p300/CBP and with the RB proteins that are bound to the DP1 and E2F transcription factors (TFs), causing the displacement of the repressive RB proteins. Small e1a-induced binding of p300/CBP and the lysine acetyltransferase PCAF at these genes causes hyperacetylation of H3K18 and probably other histone lysines, leading to transcription induction. Genes involved in differentiation, development and cell-cell signalling are bound by e1a and p107 mainly at 24 h post infection and are depleted of p300/CBP and H3K18ac, resulting in repression. The model describes average molecular events for each class; however, certain genes show expression changes and/or binding patterns that are different from the main trends illustrated here. TSS, transcriptional start site. Figure is modified, with permission, from REF. © (2008) The American Association for the Advancement of Science.