SOX2 as a New Regulator of HPV16 Transcription

Abstract

Persistent infections with high-risk human papillomavirus (HPV) constitute the main risk factor for cervical cancer development. HPV16 is the most frequent type associated to squamous cell carcinomas (SCC), followed by HPV18. The long control region (LCR) in the HPV genome contains the replication origin and sequences recognized by cellular transcription factors (TFs) controlling viral transcription. Altered expression of E6 and E7 viral oncogenes, modulated by the LCR, causes modifications in cellular pathways such as proliferation, leading to malignant transformation. The aim of this study was to identify specific TFs that could contribute to the modulation of high-risk HPV transcriptional activity, related to the cellular histological origin. We identified sex determining region Y (SRY)-box 2 (SOX2) response elements present in HPV16-LCR. SOX2 binding to the LCR was demonstrated by in vivo and in vitro assays. The overexpression of this TF repressed HPV16-LCR transcriptional activity, as shown through reporter plasmid assays and by the down-regulation of endogenous HPV oncogenes. Site-directed mutagenesis revealed that three putative SOX2 binding sites are involved in the repression of the LCR activity. We propose that SOX2 acts as a transcriptional repressor of HPV16-LCR, decreasing the expression of E6 and E7 oncogenes in a SCC context.

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

“…The LCR displayed greater sequence variability than any other region in the HPV16 genome, which was consistent with our results showing that the nucleotide variation rate of LCR was 8.17%. This region includes several binding sites for cellular and viral TFs, which regulate the replication of HPV16 and the transcriptional activity of the early regions . In the present study, 25 loci identified in the LCR of the various sequences are embedded in the putative binding sites for transcription factors TBP, Ftz, USF, Hb, Oct‐1, C/EBP α, GR_α, YY1, AP‐1, NF‐1, Pit‐1α, E2, and ICSBP.…”

“…Notably, the harmful behaviors of HPV‐positive cancer cells was greatly determined by the expression of the E6 and E7 oncogenes, but by influencing their normal biological processes it was principally reversible . The LCR contains the replication origin and cis‐responsive elements recognized by cellular and viral TFs controlling viral transcription . Therefore, we systematically analysed the genetic variability and population genetics of HPV16, nucleotide sequence, amino acid sequence, and structure of E6 and E7 genes, and prediction of transcription factor binding sites in the LCR .…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…Specifically, upon bacterial DNA stimulation, Sox2 interacts with TAB2, which causes the TAB2/TAK1 kinase complex to dimerize and lead to the activation of NF-κB and AP-1 signaling. A recent study analyzed the long control regions, which are important sites of viral replication regulation for HPV16, and found that overexpression that Sox2 can repress the E6 and E7 oncogene expression of HPV16 (Martínez-Ramírez et al, 2017). Although this study did not investigate innate immune induction by Sox2, this study highlights the role of Sox2 in mediating a DNA virus infection and will need further investigation to clarify its mechanism.…”

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

“…Some investigators found that SOX2 regulated HPV16 transcription by inhibiting activity of its long control region and finally decreasing expression of the E6 and E7 oncogenes in CC carcinogenesis 64 . Furthermore, mounting evidence implicated other members of the SOX genes family in the regulation of CC progression ( Figure 5 ) and identified their roles as biomarkers for predicting the prognosis of patients with CC ( Table 1 ).…”