A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

Abstract

The Octamer‐binding transcription factor‐4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post‐embryonic re‐expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus (HPV)‐related than HPV‐unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4‐transcriptional output and Oct4‐related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4‐protein interactions in cervical cancer cells via computational analyses and Mass Spectrometry and reveal that Methyl‐binding proteins (MBD2 and MBD3), are determinants of Oct4‐driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re‐expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate Oct4 re‐expression and global transcriptional patterns by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.