Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

HPVE6-USP46 Mediated Cdt2 Stabilization Reduces Set8 Mediated H4K20-Methylation to Induce Gene Expression Changes

ABSTRACT: Cervical cancer is one of the most common cancers in women. More than 95% of the cervical cancers are caused by the human papilloma viruses. Earlier we had identified a protein target, USP46 that can be inhibited to block the cancer growth. We found that the viral E6 and human USP46 complex increases the levels of Cdt2 in cervical cancers. In this paper we compared real cervical tumors with matched normal tissue from same patients and found that the effects of E6 mediated USP46 activation are indeed reflected as increased levels of Cdt2 and decreased levels of Set8 protein in the real tumors. We also found that the HPV protein E6 alone can stimulate the enzymatic activity of human USP46. By doing this it activates several cellular pathways that are required for the growth of cancers. One such pathway is the EGFR pathway that is normally upregulated in cervical cancers. We find that E6-USP46 contributes to the activation of EGFR by inducing epigenetic changes on the DNA by degrading the Set8 protein. These findings illuminate the role of viral E6 protein in inducing cancers and substantiate the candidature of USP46 as a drug target for HPV induced cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE191010 | GEO | 2021/12/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transgenic SCLC induced by E6/E7 oncoproteins vs normal controls

Project description:The human papillomavirus virus (HPV) is a proven cause of most human cervical cancers, and might have a role in other malignancies including vulva, skin, oesophagus, head and neck cancer. HPV has also been speculated to have a role in the pathogenesis of lung cancer. To validate the hypothesis of HPV involvement in small cell lung cancer pathogenesis we performed gene expression profile of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins. Gene expression profile of SCLC has been performed using Agilent whole mouse genome (4x44k) representing ~ 41000 genes and mouse transcripts. Samples were obtained from two HPV16-E6/E7 transgenic mouse model and from littermateM-bM-^@M-^Ys normal lung.

2014-05-27 | E-GEOD-23962 | biostudies-arrayexpress

Ecdysoneless protein regulates viral and cellular mRNA splicing to promote cervical oncogenesis

Project description:The high-risk subgroup of Human papilloma viruses (HPVs), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin, and upper aerodigestive tract. The high-risk HPV oncoproteins E6 and E7 are expressed from a polycistronic transcript that can potentially give rise to alternatively spliced E6 mRNAs, a process important for E6 and E7 expression and oncogenic transformation. Previously, we identified ECD, the human homologue of the Drosophila ecdysoneless gene, as a novel HPV16 E6-interacting protein using Yeast two-hybrid system. Here, we show that the C-terminal region of ECD selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in HPV+ as well as HPV- cervical and head and neck patient tumor samples. Using the TCGA dataset, we show that ECD mRNA overexpression predicts shorter survival in these cancer patients. Recent work from our laboratory showed that ECD associates with several components of RNA biogenesis/splicing machinery and are involved in mRNA export. Here, we show that ECD is an RNA binding protein and regulates mRNA splicing. RNAseq analyses of SiHa cells upon ECD knockdown (KD) revealed alterations of many cellular pathways with prominent downregulation of components of the mRNA splicing machinery. Further investigation revealed that ECD KD resulted in dysregulation of E6 RNA splicing, resulting in decreased E7 and increased RB protein. Furthermore, ECD KD dysregulated several cellular mRNAs known to be critical for HPV oncogenesis. Finally, we demonstrate that while ECD KD in cervical cancer cell lines led to a reduction in oncogenic traits, ECD overexpression together with E7 led to the immortalization of keratinocytes. Taken together, our results support a novel role of ECD in transcription and in viral and cellular mRNA splicing to support HPV-driven oncogenesis.

2022-06-01 | GSE174317 | 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

Transgenic SCLC induced by E6/E7 oncoproteins vs normal controls

2014-05-27 | GSE23962 | GEO

Genome-wide profiling of human gene in HPV16E2 protein expressing human keratinocyte

Project description:In the early stage of human papillomavirus (HPV) infection, E2 and E6 proteins are expressed and elicit specific immune response to clear cervical lesion. HPV E6 protein can reduce type I interferon (IFN) including IFN-? that involves in immune evasion and HPV persistence. To evaluate the role of E2 protein in modulation of the expression of cellular genes as well as innate immune associated genes in HPV associated cervical cancer, genome-wide expression profiling of human primary keratinocytes (HPK) harbouring HPV16 E2 and HPV18 E2 was investigated using microarray assay and innate immune associated genes were analyzed. These results indicated that HPV E2s altered cellular gene expression including immune associated genes. Altered cellular signaling pathways in HPK expressing HPV E2s based on KEGG database. The top 10 canonical pathways include metabolic pathway, cytokine-cytokine receptor interaction, pathway in cancer, viral carcinogenesis, protein processing in endoplasmic reticulum, PI3K-AKT signaling pathway, MAPK signaling pathway, leukocyte transendothelial migration, chemokine signaling, and focal adhesion.

2014-01-14 | GSE54008 | GEO

Quantitative proteomic analysis of tumour tissues isolated from early and late stage human cervical cancer patients

Project description:Human papillomavirus (HPV) infection related malignancy remains a severe public health problem worldwide, although HPV prophylactic vaccine has been introduced 15 years ago . HPV-associated cancers comprise 29.1% of all 2.2 million infection-related cancers, including nearly 100% of cervical cancers1 and some head and neck cancers . Cervical cancers are the 3rd most common cancer in women worldwide, HPV16 and 18 account for about 70% of cervical cancers. Moreover, high-risk HPV infection, especially HPV16 infection, is related to a proportion of head and neck epithelial carcinoma in both developed and undeveloped countries. HPV related cancers are most severe in developing countries where HPV prophylactic vaccination rates are low.In this project, we use iTRAQ8plex-labelling proteomics to comparatively study the protein contents in the tumour tissues of early and late stage cervical cancer patietns.

2023-01-26 | PXD029103 | Pride

Gene Expression Profiles of HPV-Positive and -Negative Head/Neck and Cervical Cancers

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

Systematic analysis of IL-1 cytokine signaling by high-risk HPV oncoproteins

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

Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells

Project description:Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results suggest an intact APM, and cytotoxicity despite the decreased expression of E6 and E7, suggesting that successful immunotherapies can be developed for HPV-induced cervical cancer, especially if combined with hypoxia-alleviating measures.

2022-11-16 | PXD032217 | Pride

Histone 4 Lys-20 Mono-Methylation by SET8 Mediates Wnt Target Gene Activation

Project description:Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 mono-methylation (H4K20me-1) in transcriptional regulation remains unclear. Here we show that Wnt3a specifically stimulates H4K20 mono-methylation at TBE (TCF-binding element) via the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with TCF4/LEF1 directly, and this interaction is regulated by Wnt3a. Therefore, we conclude that SET8 is a Wnt signaling mediator and is recruited by LEF1/TCF4 to regulate the transcription of Wnt-activated genes, possibly via H4K20 mono-methylation at the target gene promoters. Our findings also indicate that H4K20me-1 is a marker for gene transcription activation, at least in canonical Wnt signaling. This chip experiment was carried out to find out how many genes would be regulated by SET8 after Wnt3a CM stimulated HEK293 cells. Total RNA was extracted from HEK293 cells after siRNA transfection (control or SET8 shRNA) for about 40 hours and then induced with Control or Wnt3a CM for 7 hours using TRIzol (Invitrogen) and the RNeasy kit (Qiagen). Three pairs of samples: si-control + control CM / si-control + Wnt3a CM 7 h / si-SET8 + Wnt3a CM. Samples were amplified and labeled using a NimbleGen One-Color DNA Labeling Kit.

2010-12-29 | E-GEOD-24708 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data