Dataset Information

P53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells.

ABSTRACT: Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7-oncogenes as drivers for proliferation remained inhibited under hypoxia.

SUBMITTER: Zhuang L

PROVIDER: S-EPMC7765197 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells.

Zhuang Linhan L Ly Regina R Rösl Frank F Niebler Martina M

International journal of molecular sciences 20201215 24

Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 <i>E6/E7</i> oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, dur ...[more]

PMID: 33333786

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Project description:It has been reported that >90% of women with cervical cancer are human papillomavirus (HPV)-positive, with HPV16 and 18 being the most 'highest-risk' HPV genotypes. However, in numerous women, HPV infection will not progress to cervical cancer. Accordingly, more appropriate screening markers need to be explored. In the present study, genome-wide DNA methylomic differences between cervical cancer tissues with HPV-16 or HPV-18 infection and normal cervical tissues were detected by using an Illumina Human Methylation 850 K BeadChip. The Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted in order to define the nearest neighbouring genes of differentiated methylation sites. Moreover, differentiated methylation sites were verified using pyrosequencing. KEGG analyses suggested that the focal adhesion pathway and pathways in cancer were highly enriched. Bioinformatics and statistical analysis indicated that the nine CpG loci had the most significant differences amongst the genes involved in these pathways. Among these, six CpG sites in the CHRM2, LAMA4, COL11A1, FGF10, IGF1 and TEK genes were highly associated with HPV-16-positive cervical cancer, as validated using pyrophosphate sequencing. Additionally, 10 significantly different CpG sites of the HPV-18-positive group were selected and verified in The Cancer Genome Atlas, indicating their possible diagnostic roles in cervical cancer development and determination. In addition, eight hypermethylated CpG island sites that were associated with HPV-16-positive cervical cancer tissues and 10 hypermethylated CpG island sites that were associated with HPV-18-positive cervical cancer tissues were identified, highlighting their potential roles in screening and evaluating targeted therapy efficacy and prognosis. The main focus of the present study was to identify the genetic variability in HPV-16- and HPV-18-positive samples and to elucidate possible methylation biomarkers in HPV-positive women with a risk of developing cervical cancer.

Dataset Information

P53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells.

Publications

p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells.

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