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Covalent inhibitors of human papillomavirus type 16 E6 protein restore p53 function and suppress growth of HPV-driven tumors in vivo

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308563 | GEO | 2026/05/22

REPOSITORIES: GEO

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Expression data from N/Tert-HPV E6 cells in the presence and absence of mitomycin C treatment

2013-09-05 | GSE50568 | GEO

Expression data from N/Tert-HPV E6 cells in the presence and absence of mitomycin C treatment

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

Proteomic Analysis of the E6 Interactome in Response to Anisomelic Acid Treatment

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

Structural dynamics of the E6AP/UBE3A-E6-p53 enzyme-substrate complex

Project description:Deregulation of the ubiquitin ligase E6AP is causally linked to the development of human disease, including cervical cancer. In complex with the E6 oncoprotein of human papillomaviruses, E6AP targets the tumor suppressor p53 for degradation, thereby contributing to carcinogenesis. Moreover, E6 acts as a potent activator of E6AP by a yet unknown mechanism. However, structural information explaining how the E6AP-E6-p53 enzyme-substrate complex is assembled, and how E6 stimulates E6AP, is largely missing. We therefore developed and applied different approaches in structural mass spectrometry to show that binding of E6 induces conformational rearrangements in E6AP, which result in the positioning of E6 and p53 in the immediate vicinity of the catalytic centre of E6AP. Our data provides structural and functional insights into the dynamics of the full-length E6AP-E6-p53 enzyme-substrate complex and reveals how E6 can both stimulate the ubiquitin ligase activity of E6AP and facilitate the transfer of ubiquitin from E6AP onto p53.

2018-10-23 | PXD010002 | Pride

HPV16 E7 Interactome Proteomics After Anisomelic Acid Treatment

Project description:Human papillomavirus (HPV) is a major cause of cervical and other anogenital cancers, with the viral oncoprotein E6 playing a central role in carcinogenesis. We previously demonstrated that anisomelic acid treatment reduces E7 protein levels in HPV-positive cancer cells. Here, we employed mass spectrometry-based proteomics to characterize changes in the HPV16 E7 interactome in normal oral keratinocytes following anisomelic acid treatment.

2025-12-10 | PXD069948 | Pride

E5 human papillomavirus type 16 oncoprotein modify ST3GAL3 and ST6GAL1 gene expression

Project description:Human papillomavirus (HPV) is the etiological agent of cervical cancer. Three viral proteins, E5, E6 and E7 have been implicated in cell transformation. Increased expression of sialic acid and sialylated antigens have been reported during cervix transformation, these results agree with the increased mRNA levels of the sialyltransferases genes ST6GAL1 and ST3GAL3 reported in premalignant and malignant tissue of the cervix. E6 and E7 HPV oncoproteins modify the expression of some glycogenes. The role of E5 HPV oncoprotein in the glycogene expression changes in premalignant and malignant cervical tissue has not been reported. The objective of this work was to identify glycogenes that modify their expression by E5 HPV oncoprotein in HaCaT cell line. A gene expression microarray was performed on HaCaT cells that stably expressed the HPV16 E5 oncogene. Analysis revealed alteration in some glycogenes including upregulation of ST6GAL1 and ST3GAL3. The increased mRNA levels of both genes were confirmed by qRT-PCR. In addition, an in-silico analysis was performed to identify glycosylation networks altered in presence of E5 oncoprotein. The analysis showed that E5 could modify the sialic acid expression, keratan sulfate synthesis, N-glycosylation and biosynthesis of glycosaminoglycans. This is the first report of the role of HPV16 E5 oncoprotein on glycogenes expression changes. Moreover, our results suggest that the increase of the sialyltransferases genes reported in premalignant and malignant cervical tissue, could be the result of the expression of E5 oncoprotein. These results provide information of the possible role of HPV infection on the sialylation changes in the cervical epithelium identified in premalignant lesions and cancer.

2018-08-21 | GSE118776 | GEO

Human Papillomavirus (HPV) genomic integration, expression and E6/E7 splicing patterns in cervical cancer associated with HPV16 or HPV18 infection

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

A ubiquitin variant-based affinity approach selectively identifies substrates of the ubiquitin ligase E6AP in complex with HPV-11 E6 or HPV-16 E6

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

Impact of HPV16 E6 and E7 oncogenes together with Chlamydia trachomatis infection on proteome changes in immortalized oral keratinocytes

Project description:Certain types of Human papilloma viruses (HPV) are the etiological agents for cervical cancer. However, not all infections of high-risk HPVs will finally lead to cancer since most HPV infections are cleared without any consequences. Chlamydia trachomatis is the most prevalent sexual transmitted bacteria and is an obligatory intracellular pathogen exhibiting tropism in endocervical epithelial cells. Over the past decades, C. trachomatis is thought to be a potential co-factor for cervical cancer formation, but there are also studies that did not show such a correlation. To address this question in molecular terms, we stably expressed HPV16 E6 and E7 in spontaneously immortalized NOKs (normal oral keratinocytes) and performed SILAC (stable isotope labeling by amino acids in cell culture) with or without C. trachomatis infection to study the impact of HPV16 oncogene expression and C. trachomatis infection on host proteome changes.

2019-03-18 | PXD012186 | Pride

Changes in global gene expression profiles induced by HPV 16 E6 oncoprotein variants in cervical carcinoma C33-A cells

Project description:We analyzed the effects of the expression of HPV 16 E6 oncoprotein variants (AA-a, AA-c, E-A176/G350, E-C188/G350, E-G350), and the E- Prototype in global gene expression profiles in an in vitro model. E6 gene was cloned into an expression vector fused to GFP and was transfected in C33-A cells. Affymetrix GeneChip Human Transcriptome Array 2.0 platform was used to analyze the expression of over 245,000 coding transcripts. We found that HPV16 E6 variants altered the expression of 431 genes in comparison with EPrototype. The altered genes are involved in cellular processes related to the development of cervical carcinoma, such as adhesion, angiogenesis, apoptosis, differentiation, cell cycle, proliferation, transcription and protein translation. Our results show that polymorphic changes in HPV16 E6 natural variants are sufficient to alter the overall gene expression profile in C33-A cells, explaining in part the observed differences in oncogenic potential of HPV16 variants.

2015-11-20 | GSE73761 | GEO

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