Previously undescribed effects and mechanisms of STAT3 in HPV-induced DNA re-replication in response to DNA damage.

Abstract

Polyploidy is an important inducer of cervical carcinogenesis. However, the mechanism by which the HPV E7 oncoprotein induces cells to cross the cell cycle checkpoint and enter G2 phase for DNA re-replication remains unclear. We have previously identified the role of WDHD1 in viral oncogene-induced re-replication. Here, we demonstrated that HPV E7 activates STAT3 signaling to drive transcriptional upregulation of two replication mediators: WDHD1, a DNA replication initiation factor, and UHRF1, an epigenetic regulator. Mechanistically, STAT3 directly activates WDHD1 gene expression while UHRF1 post-transcriptionally stabilizes WDHD1, forming a feedforward loop that enables G2-phase re-replication and polyploidy. This study reveals a novel STAT3-WDHD1-UHRF1 regulatory axis, driving HPV E7-induced polyploid genomic instability. Given the limited number of genes known to induce DNA re-replication, these findings reveal HPV E7-induced polyploidy as a STAT3-dependent process involving multilayer regulatory crosstalk and provide new therapeutic targets to counteract viral oncogenesis.