High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis

Abstract

Infection with high-risk human papillomavirus (HPV) has been linked to several human cancers, the most prominent of which is cervical cancer. The integration of the viral genome into the host genome is one of the manners in which the viral oncogenes E6 and E7 achieve persistent expression. The most well-studied cellular targets of the viral oncogenes E6 and E7 are p53 and pRb, respectively. However, recent research has demonstrated the ability of these two viral factors to target many more cellular factors, including proteins which regulate epigenetic marks and splicing changes in the cell. These have the ability to exert a global change, which eventually culminates to uncontrolled proliferation and carcinogenesis.

Keywords: E6; E7; HPV; cervical cancer; human papillomavirus; viral oncogenes; viral-induced cancers.

Figure 1

E6 regulates many cellular targets through E6AP and E6′s PDZ-binding motif. Some of these targets are depicted above. Upon the abrogation of the sites on E6 which are involved in the interaction of E6AP and PDZ-containing proteins respectively, there are drastic phenotypic consequences.

Figure 2

The HPV oncogene E7 is able to regulate multiple epigenetic factors such as DNMT1, HDAC1, and EZH2. E7 associates with DNMT1 on the promoter region of CCNA1, resulting in its hypermethylation, and therefore repression. E7 is also able to regulate the repressive H3K27Me3 mark through several of its upstream factors. By binding to the repressive E2F6, E7 is able to de-repress the transcription of the methyltransferase EZH2. Conversely, E7 was shown to transcriptionally upregulate KDM6A/B, demethylases of H3K27Me3. Further, E6 and E7 has also been shown to recruit AKT to phosphorylate and therefore inactivate EZH2. Lastly, E7 is able to cooperate with HDAC, resulting in the tri-methylation of H3K4 and the acetylation of H3K9 on the promoter of E2F1 to upregulate the transcription of E2F1.

Figure 3

HPV oncogenes E6 and E7 target a plethora of cellular factors. This eventuates in cell cycle progression, evasion of apoptosis, DNA damage, and the suppression of the host cell immune response.