HPV16 activates the promoter of Oct4 gene by sequestering HDAC1 from repressor complex to target it to proteasomal degradation

Abstract

Human papillomavirus 16 (HPV16) is the key factor to initiate cervical carcinogenesis and development. Octamer-binding transcription factor 4 (Oct4) is an important transcriptional factor which is up-regulated in some cancer cells. Our study showed that the expression of Oct4 might be activated by HPV16 infection. Both the levels of histone deacetylase 1 (HDAC1) and DNA methyltransferase 3A (DNMT3A) were negatively correlated with the level of Oct4 in cervical cancer cells. Moreover, HDAC1 and DNMT3A proteins were in the same complex, the level of which was higher in the presence of HPV16. The treatment with HDAC1 inhibitor reduced the level of this complex, followed by the upregulation of Oct4 expression. Based on these findings and previous reports, we hypothesize that a repressor complex containing methyl CpG-binding domain protein 2 (MBD2), DNMT3A and HDAC1 binds to the hyper-methylated regulatory regions of Oct4 gene to facilitate forming a close chromatin which results in the suppression of Oct4 transcription in cervical cells. The oncoproteins of HPV16 synergistically sequester HDAC1 protein from repressor complex, and target it to ubiquitin mediated proteasome degradation. The repressor complex is thus destroyed and the close chromatin is relaxed, which eventually lead to the upregulation of Oct4 expression.