Effect of folate deficiency on human papillomavirus-induced carcinogenesis

SAVINI, CLAUDIA; GÖCKEL-KRZIKALLA, ELKE; VINZON, SABRINA EUGENIA; RÖSL, FRANK

Basilea

Congreso; Viruses 2016 - At the Forefront of Virus-Host Interactions; 2016

Several epidemiological studies highlighted the importance of micronutrient intake in cancer development. Folate, a water soluble B vitamin, has been shown to exert a protective effect in carcinogenesis. Deficiency in folate is associated with an increased incidence of several cancers, including cervical cancer, that is etiologically linked to Human Papilloma Virus (HPV) infection. In our study we aim to identify the molecular events upon folate deficiency that can promote HPV-induced carcinogenesis. Using HPV16E6E7-immortalized human keratinocytes, we observed that in vitro depletion of folate had an impact on cellular growth. Interestingly, cells cultured in low folate medium had an increased ratio of cells in the S-phase of cell cycle, in correlation with the activation of DNA damage response markers such as gH2AX. Additionally, genome wide methylation analysis of these cells showed that in vitro folate deficiency induced deregulation of the methylation profile, affecting numerous CpG islands within gene promoters. This result indicates that folate deficiency can also affect gene expression in HPV-immortalized keratinocytes in epigenetic terms. Furthermore, folate repletion in the culture medium led to higher growth rate and plating efficiency than the control cells, highlighting acquired pro-proliferative features during the folate deficiency period. Taken together, these observations suggest that folate deficiency may play a role as a cofactor in HPV-induced carcinogenesis. Further investigation is being conducted to characterize the molecular mechanisms underlying the observed events.