Residual p53 in HPV positive cervical cancer cells has gain of function properties
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325258 | GEO | 2026/05/13
REPOSITORIES: GEO
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Project description:High-risk human papillomavirus (HPV) infections are the etiology of approximately 5% of all cancers worldwide, including cervical, anal, and oropharyngeal malignancies. HPV E6 is a multifunctional oncoprotein that drives tumorigenesis and is best known for bridging the ubiquitin ligase E6AP (UBE3A) and p53 into a complex that leads to proteasome mediated destruction of p53. We developed small molecule inhibitors that covalently bind to cysteine-51 (Cys-51) in HPV16 E6. In HPV16-positive cancer cells, these compounds increase p53 protein levels and activate p53-dependent transcriptional programs associated with apoptosis and senescence, resulting in reduced tumor cell viability. In vivo, E6 inhibition suppresses the growth of human HPV16 expressing cervical and oropharyngeal tumor cell lines in mice. The strategy of targeting a viral oncoprotein with a covalent inhibitor demonstrates a genotype-specific therapeutic strategy for HPV-associated cancers and premalignant infections, addressing a significant unmet need in current treatment options.
2026-05-22 | GSE308563 | GEO
Project description:Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1beta. Models of early-stage HPV infection (human keratinocytes expressing HPV16 E6 and E7) and models of established HPV-positive head and neck cancers (patient-derived xenografts, head and neck cancer cell lines) exhibited similar dysregulation of IL-1 pathway genes and suppressed responses to IL-1beta treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1beta-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.
2022-10-31 | GSE211730 | GEO
Project description:Human papillomavirus (HPV) genome integration into the host genome, blocking E2 expression and leading to overexpression of E6 and E7 viral oncogenes, is considered a major step in cervical cancer development. In high-risk HPVs, E6 and E7 oncogenes are expressed as a bicistronic pre-mRNA, with alternative splicing producing the ultimate mRNAs required for E6 and E7 translation. Given the number of alternative donor and acceptor splicing sites, ten E6/E7 different alternative transcripts might be formed for HPV16 and three for HPV18, although only six isoforms have been previously reported for HPV16. In the present work, we employ high-throughput sequencing of invasive cervical cancer transcriptome (RNA-Seq) to characterize the expression of the HPV genome in 24 invasive cervical cancers associated with HPV16 and HPV18 single infections. Based on high-resolution transcriptional maps, we herein report three viral gene expression patterns which might be associated with the presence of the viral genome in episomal and/or integrated stages. Alternative mRNAs splicing isoforms coding for E6 and E7 oncoproteins were characterized and quantified, and two novel isoforms were identified. Three major isoforms (E6*I, E6*II, and E6+E7) were detected for HPV16 and two for HPV18 (E6*I and E6+E7). Minor transcript isoforms, including the novel ones, were very rare in some tumor samples or were not detected. Our data suggested that minor transcript isoforms of E6/E7 do not play a relevant role in cervical cancer.
2019-08-06 | GSE91065 | GEO
Project description:HPV E6 from the genus alpha 'high risk' types such as HPV16 recruit the ubiquitin ligase E6AP to ubiquitinate p53 and target it for proteasome-mediated degradation. This results in the functional inactivation of p53 in HPV16-E6 expressing cells. To test what patterns in gene expression might change as a result of HPV16 E6 protein functions and to test whether HPV E6 proteins from genus beta virus types also inactivate p53, we profiled gene expression using Affymetrix arrays before and after stimulating p53 activity via DNA damage in a panel of N/Tert-E6 cell lines.
2013-09-05 | GSE50568 | GEO
Project description:The E6 protein of both mucosal high risk human papillomaviruses (HPVs) such as HPV-16, which have been causally associated with malignant tumors, and low risk HPVs such as HPV-11, which cause the development of benign tumors, interacts with the cellular E3 ubiquitin ligase E6AP. This indicates that both HPV types employ E6AP to organize the cellular proteome to viral needs. However, while several substrate proteins of the high risk E6-E6AP complex are known, e.g. the tumor suppressor p53, potential substrates of the low risk E6-E6AP complex remain largely elusive. Here, we report on an affinity-based enrichment approach that enables the targeted identification of potential substrate proteins of the different E6-E6AP complexes by a combination of E3-selective ubiquitination in whole cell extracts and high-resolution mass spectrometry. The basis for the selectivity of this approach is the use of a ubiquitin variant that is efficiently used by the E6-E6AP complexes for ubiquitination, but not by E6AP alone. By this approach, we identified approximately 190 potential substrate proteins for low risk HPV-11 E6 as well as high risk HPV-16 E6. Moreover, subsequent validation experiments in vitro and within cells with selected substrate proteins demonstrate the potential of our approach. In conclusion, our data represent a reliable repository for potential substrates of the HPV-16 and HPV-11 E6 proteins in complex with E6AP.
2020-08-31 | PXD020660 | Pride
Project description:HPV E6 from the genus alpha 'high risk' types such as HPV16 recruit the ubiquitin ligase E6AP to ubiquitinate p53 and target it for proteasome-mediated degradation. This results in the functional inactivation of p53 in HPV16-E6 expressing cells. To test what patterns in gene expression might change as a result of HPV16 E6 protein functions and to test whether HPV E6 proteins from genus beta virus types also inactivate p53, we profiled gene expression using Affymetrix arrays before and after stimulating p53 activity via DNA damage in a panel of N/Tert-E6 cell lines. N/Tert-1 human keratinocyte cell lines were cultured in K-SFM (Invitrogen) and treated with 2 ug/ml mitomycin C or with vehicle control for 18 hours. RNA isolated from frozen cell pellets was analyzed on Affymetrix arrays. Each cell line was grown and processed on arrays in 3-5 separate experiments.
2013-09-05 | E-GEOD-50568 | biostudies-arrayexpress
Project description:Human papillomaviruses (HPVs) are associated with nearly all cervical cancers (CCs), 20-30% of head and neck cancers (HNCs), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, CCs and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV+HNCs and CCs differed in their patterns of gene expression yet shared many changes compared to HPV-HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV+HNCs and CCs were found to be upregulated in their expression of a distinct and larger subset of cell cycle genes than observed in HPV-HNC. Moreover, HPV+ cancers over-expressed testis-specific genes that are normally expressed only in meiotic cells. Many, though not all, of the hallmark differences between HPV+HNC and HPV-HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testes specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV+ and HPV- cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV+ cancers. Keywords: Gene expression ptofiles of primary cancers
2007-05-15 | GSE6791 | GEO
Project description:Epigenetic alterations are a key hallmark of cancer and are increasingly recognized as promising clinical biomarkers and therapeutic targets. In recent years Head and Neck Squamous Cell Carcinomas (HNSCC) have been classified into two subtypes: HPV-positive (HPV+), driven by human papillomavirus (HPV) infections, and the HPV-negative (HPV-), associated with environmental risk factors. Although exhibiting distinct molecular and clinicopathological features, both subtypes lack effective, tailored therapies. Thus, profiling their epigenetic landscape could thus have important clinical implications. In this study, we employed a quantitative mass spectrometry approach to profile histone post-translational modification (hPTMs) in HPV+ and HPV- HNSCC. We found that the histone mark H3K36me2 is significantly enriched in the HPV+ subtype and that this alteration is driven by hr-HPV E6/E7 oncoproteins which also upregulate NSD2, a histone methyltransferase specific for H3K36 dimethylation. Both H3K36me2 and NSD2 are upregulated in several cancers. Given the NSD2’s context and cell-type-dependent functions, we investigated its role in HPV+ and HPV- HNSCC. We observed that NSD2 regulates cell proliferation and migration in both the subtypes. Importantly, we identified a novel role for NSD2 in regulating epithelial cell differentiation, particularly in HPV+ HNSCC, where it appears to modulate the E6/E7-induced differentiation blockade. Overall, our findings highlight H3K36me2 as a potential biomarker for patient stratification and position NSD2 as a promising therapeutic target across HNSCC subtypes, regulating both shared and subtype-specific oncogenic pathways. Specifically, NSD2 inhibition in HPV+ tumors may restore epithelial differentiation and arrest tumor progression.
2026-02-11 | GSE313615 | GEO
Project description:Human papillomavirus (HPV) is a well-known cause of cervical cancer, with the viral oncoprotein E6 playing a key role in carcinogenesis. We previously showed that anisomelic acid treatment reduces E6 protein levels in HPV-positive cancer cells. In this study, we used mass spectrometry-based proteomics to investigate how anisomelic acid affects the HPV16 E6 interactome in normal oral keratinocytes.
2025-09-22 | PXD065382 | Pride
Project description:Purpose: There is substantial heterogeneity within the human papillomavirus (HPV) positive head and neck cancer (HNC) tumors that predispose them to different outcomes, however this subgroup is poorly characterized due to various historical reasons. Experimental Design: we perform unsupervised gene expression clustering on well-annotated HPV(+) HNC samples from two cohorts ( 84 total primary tumors), as well as 18 HPV(-) HNCs, to discover subtypes, and begin to characterize the differences between the subtypes in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number variations and mutation frequencies. Results: We identified two distinctive HPV(+) subtypes by unsupervised clustering. Membership in the HPV(+) subtypes correlates with genic viral integration status, E2/E4/E5 expression levels and the ratio of spliced to full length HPV oncogene E6. The subtypes also show differences in copy number alterations, in particular the loss of chr16q and gain of chr3q, PIK3CA mutation, and in the expression of genes involved in several biological processes related to cancer, including immune response, oxidation-reduction process, and keratinocyte and mesenchymal differentiation. Conclusion: Our characterization of two subtypes of HPV(+) tumors provides valuable molecular level information in relation to the alternative paths to tumor development and to that of HPV(-) HNCs. Together, these results will shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients. 36 head and neck primary tumors (18 HPV+ and 18 HPV-) and their matched blood samples were collected and genotyped by Illumina OmniExpress SNP array. RNA-seq was also performed on the same set of tumor samples.
2016-05-13 | E-GEOD-74927 | biostudies-arrayexpress