Human papillomavirus type 16 (HPV16) and type 18 (HPV18) are the two most prevalent high-risk HPVs for causing cervical cancer—a cancer that claims the lives of more than 250,000 women around the world every year. They transform healthy keratinocytes — cells that line the cervix — into cancerous cells by disrupting the host cell cycle. In particular, they use viral genes E6 and E7 to encode proteins E6 and E7 that bind and inactivate tumor-suppressor proteins p53 and pRb, respectively.
As E6 and E7 proteins of different high-risk HPVs have similar functions, however, the reason for HPV18 having a higher potential for causing cervical cancer is still unknown. Francoise Thierry at the A*STAR Institute of Medical Biology and co-workers have now solved this mystery through a study of the transcriptional regulation of E6 and E7.
E2F is a family of transcription factors that regulate the transcription of S-phase and mitotic genes, which are essential for cell duplication and division. There are eight members in the E2F family: E2F1–3 are activators and E2F4–8 are repressors. In normal keratinocytes, pRb binds to E2F1–3 and prevents them from activating the transcription of S-phase genes, whereas E2F5 suppresses the transcription. In HPV-infected keratinocytes, however, E7 binds to pRb and prevents it from binding to E2F1–3. As a result, E2F1–3 activate the transcription of S-phase genes, allowing the infected keratinocytes to multiply uncontrollably.
The researchers compared the HPV genomes and identified an E2F5-binding site on the E7 promoter of HPV18. They showed that in HPV18-infected keratinocytes, E2F5 binds and activates the transcription of E7. As a result, more pRb becomes inactivated and more E2F activators become available for activating S-phase genes.
In essence, HPV18 changes the role of E2F5 from being a repressor to an activator. The exclusivity of the E2F5-binding site on E7 to HPV18 is one explanation for why HPV18 has a higher potential to cause cervical cancer than other high-risk HPVs.
“Cervical cancer is a major killer of women worldwide and is caused by HPVs. Vaccines may soon reduce HPV infections but the time lag between infection and cancer is long, and many young women will die before this killer cancer virus is stopped. The aim of our research is to describe viral proteins interactions with the host cell and hence define new therapeutic targets to fight the disease,” says Thierry.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology.