Methylation of the human papillomavirus-18 L1 gene: a biomarker of neoplastic progression?

Tolga Turan, Mina Kalantari, Itzel E Calleja-Macias, Heather A Cubie, Kate Cuschieri, Luisa L Villa, Hanne Skomedal, Hugo A Barrera-Saldaña, Hans-Ulrich Bernard

Research output: Contribution to journalArticlepeer-review


Epigenetic transcriptional regulation plays an important role in the life cycle of human papillomaviruses (HPVs) and the carcinogenic progression of anogenital HPV associated lesions. We performed a study designed to assess the methylation status of the HPV-18 genome, specifically of the late L1 gene, the adjacent long control region (LCR), and part of the E6 oncogene in cervical specimens with a range of pathological diagnoses. In asymptomatic infections and infections with precancerous (precursor) lesions, HPV-18 DNA was mostly unmethylated, with the exception of four samples where hypermethylation of L1 was detected. In contrast, L1 sequences were strongly methylated in all cervical carcinomas, while the LCR and E6 remained unmethylated. HeLa cells, derived from a cervical adenocarcinoma, contain chromosomally integrated HPV-18 genomes. We found that L1 is hypermethylated in these cells, while the LCR and E6 are unmethylated. Treatment of HeLa cells with the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) led to the expected reduction of L1 methylation. After removal of 5-Aza-CdR, L1 methylation resumed and exceeded pretreatment levels. Unexpectedly, the LCR and E6 also became methylated under these conditions, albeit at lower levels than L1. We hypothesize that L1 is preferentially methylated after integration of the HPV genome into the cellular DNA, possibly since linearization prohibits its normal transcription, while the enhancer and promoter may be protected from methylation by transcription factors. Since our data suggest that HPV-18 L1 methylation can only be detected in carcinomas, except in some few precancerous lesions and asymptomatic infections, L1 methylation may constitute a powerful molecular marker for detecting this important step of neoplastic progression.
Original languageEnglish
Pages (from-to)175-83
Number of pages9
Issue number1
Publication statusPublished - 25 May 2006


  • Azacitidine
  • Capsid Proteins
  • Cervix Uteri
  • DNA Methylation
  • DNA Modification Methylases
  • DNA, Viral
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Female
  • HeLa Cells
  • Humans
  • Oncogene Proteins, Viral
  • Papillomaviridae
  • Proviruses
  • Regulatory Elements, Transcriptional
  • Tumor Markers, Biological
  • Uterine Cervical Neoplasms
  • Viral Proteins


Dive into the research topics of 'Methylation of the human papillomavirus-18 L1 gene: a biomarker of neoplastic progression?'. Together they form a unique fingerprint.

Cite this