Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer (Review)

Abstract

Human papillomaviruses (HPVs) are double stranded circular DNA viruses that infect cutaneous and mucosal epithelial cells. Almost 99% of cervical cancer has a HPV infection. The early oncoproteins E6 and E7 are important in this cellular transformation process. Epigenetic mechanisms have long been known to result in decisive alterations in DNA, leading to alterations in DNA-protein interactions, alterations in chromatin structure and compaction and significant alterations in gene expression. The enzymes responsible for these epigenetic modifications are DNA methyl transferases (DNMTs), histone acetylases and deacetylases. Epigenetics has an important role in cancer development by modifying the cellular micro environment. In this review, the authors discuss the role of HPV oncoproteins E6 and E7 in modulating the epigenetic mechanisms inside the host cell. The oncoproteins induce the expression of DNMTs which lead to aberrant DNA methylations and disruption of the normal epigenetic processes. The E7 oncoprotein may additionally directly bind and induce methyl transferase activity of the enzyme. These modulations lead to altered gene expression levels, particularly the genes involved in apoptosis, cell cycle and cell adhesion. In addition, the present review discusses how epigenetic mechanisms may be targeted for possible therapeutic interventions for HPV mediated cervical cancer.

Analysis of the Role of the Human Papillomavirus 16/18 E7protein Assay in Screening for Cervical Intraepithelial Neoplasia: A Case Control Study

“…Hr-HPV E7 protein inhibits retinoblastoma protein, thereby promoting the uncontrolled proliferation and malignant transformation of infected cells (8,9). Sustained E7 protein expression is the pathological basis for CIN and cervical cancer (10)(11)(12). Therefore, E7 protein may be a marker for CIN (13,14).…”

DNA methyltransferases in virus‐associated cancers

“…E6 and E7 interact with different pathways to activate DNMTs. Proposed pathways for E6 and E7 include (1) indirect mechanism by specificity protein 1 (Sp1) and E2F, respectively, and (2) direct pathway mediated by E7 . Evidence have attributed the antiapoptotic characterizations of HPV to E6 protein .…”

“…E7 interacts with Rb in RB‐E2F complex, leading to E2F release that forms E2F/DNMT complex and initiates CpG hypermethylation. In direct role, E7 also binds directly to DNMT1 and performs its stimulating effect . Yeungk et al showed that knockdown of HPV‐16 E6 in cervical carcinoma cell lines results in increased level of p53 and downregulation of DNMT1 that suggests that DNMT1 level is repressed by p53 .…”

“…VP, viral protein; TSGP, tumor suppressor gene promoter; DP, DNMT promoter; C, cytosine; 5mc, 5 methyl-cytosine include (1) indirect mechanism by specificity protein 1 (Sp1) and E2F, respectively, and (2) direct pathway mediated by E7. 30 Evidence have attributed the antiapoptotic characterizations of HPV to E6 protein. 31 E6 is able to affect p53 by ubiquitination and degradation.…”

“…In direct role, E7 also binds directly to DNMT1 and performs its stimulating effect. 30 Yeungk et al showed that knockdown of HPV-16 E6 in cervical carcinoma cell lines results in increased level of p53 and downregulation of DNMT1 that suggests that DNMT1 level is repressed by p53. 25 On the other hand, methylation of proteins which are implicated in apoptotic response such as p53 is suggested in cervical cancer.…”