Human papillomavirus E7 induces p63 expression to modulate DNA damage response

Eldakhakhny, Sahar; Zhou, Qing; Crosbie, Emma J.; Sayan, Berna S.

doi:10.1038/s41419-017-0149-6

Cited by 18 publications

(14 citation statements)

References 65 publications

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“…Furthermore, initial analysis of RNA-Seq and SILAC data identified factors (Table S3) that were already shown to be affected by HPV in multiple previous studies, including the upregulated genes IL1A (39), UCHL1 (40), TYMS (41), EGFR (42), TP63 (43), and PCNA (44) and the downregulated genes STAT1 (45), FN1 (46), and ISG15 (47). In other words, the validation of aforementioned findings served as an internal reference for the reliability of this cell system to identify new factors with important functions in HPV-related cancers.…”

Section: Resultsmentioning

confidence: 89%

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Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis

Yang

Klimentová

Göckel-Krzikalla

et al. 2019

mSphere

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Although the role of high-risk human papillomaviruses (hrHPVs) as etiological agents in cancer development has been intensively studied during the last decades, there is still the necessity of understanding the impact of the HPVE6andE7oncogenes on host cells, ultimately leading to malignant transformation. Here, we used newly established immortalized human keratinocytes with a well-defined HPV16E6E7expression cassette to get a more complete and less biased overview of global changes induced by HPV16 by employing transcriptome sequencing (RNA-Seq) and stable isotope labeling by amino acids in cell culture (SILAC). This is the first study combining transcriptome and proteome data to characterize the impact of HPV oncogenes in human keratinocytes in comparison with their virus-negative counterparts. To enhance the informative value and accuracy of the RNA-Seq data, four different bioinformatic workflows were used. We identified potential novel upstream regulators (e.g., CNOT7, SPDEF, MITF, and PAX5) controlling distinct clusters of genes within the HPV-host cell network as well as distinct factors (e.g., CPPED1, LCP1, and TAGLN) with essential functions in cancer. Validated results in this study were compared to data sets from The Cancer Genome Atlas (TCGA), demonstrating that several identified factors were also differentially expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and HPV-positive head and neck squamous cell carcinomas (HNSCs). This highly integrative approach allows the identification of novel HPV-induced cellular changes that are also reflected in cancer patients, providing a promising omics data set for future studies in both basic and translational research.IMPORTANCEHuman papillomavirus (HPV)-associated cancers still remain a big health problem, especially in developing countries, despite the availability of prophylactic vaccines. Although HPV oncogenes have been intensively investigated for decades, a study applying recent advances in RNA-Seq and quantitative proteomic approaches to a precancerous model system with well-defined HPV oncogene expression alongside HPV-negative parental cells has been missing until now. Here, combined omics analyses reveal global changes caused by the viral oncogenes in a less biased way and allow the identification of novel factors and key cellular networks potentially promoting malignant transformation. In addition, this system also provides a basis for mechanistic research on novel key factors regulated by HPV oncogenes, especially those that are confirmedin vivoin cervical cancer as well as in head and neck cancer patient samples from TCGA data sets.

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Section: Resultsmentioning

confidence: 89%

“…3), we focused on transcriptional regulators because their activity changes can affect multiple downstream targets. In addition to STAT1 , HIF1α , and TP63 , which have been reported to be affected by HPV before (43, 45), pathway analysis predicted CNOT7 , SPDEF , MITF , PAX5 , and HIC1 as major novel regulators (Fig. 4 and 5).…”

Section: Resultsmentioning

confidence: 91%

Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis

Yang

Klimentová

Göckel-Krzikalla

et al. 2019

mSphere

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“…PIR2 expression was analysed with the primers: FL-PIR2-F: 5′-ATGGGCTCAGCTGGTAGGC-3′ and FL-PIR2-R: 5′-GGTTGTGGATGGGTCGTGCT-3′. The amplified DNA fragments were analysed as described previously 60 .…”

Section: Methodsmentioning

confidence: 99%

Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation

et al. 2018

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Endometrial cancer is one of the most common gynaecological cancers in developed countries. Its incidence has increased 20% over the last decade and the death rate has increased >100% over the past two decades. Current models for prediction of prognosis and treatment response are suboptimal, and as such biomarkers to support clinical decision-making and contribute to individualised treatment are needed. In this study, we show that the E3-ubiquitin ligase PIR2/RNF144B is a potential targetable biomarker in endometrial cancer. At transcript level, it is expressed both in normal endometrium and tumour samples, but at protein level, it is expressed in tumours only. By using endometrial cancer cell lines, we demonstrated that PIR2/RNF144B is stabilised via phosphorylation downstream of GSK3β and this is necessary for the proliferation of endometrial cancer cells, in the absence of oestrogenic growth stimuli. Here, inactivation of GSK3β activity is associated with loss of PIR2/RNF144B protein and consequent inhibition of cell proliferation. Our results, therefore, substantiate PIR2/RNF144B as a novel candidate for targeted therapy in endometrial cancer.

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“…In HPV-positive keratinocytes depleted of p63, the levels of cell cycle regulatory proteins, such as cyclin A, cyclin B1, cdk1, and cdc25c, were reduced and late viral activities were impaired [181]. p63 protein levels are elevated in cervical cancer cell lines, dependent on HPV E7, and there is a good correlation between high p63 staining and HPV positivity in cervical lesions [182,183].…”

Section: High-risk Hpv Oncoproteins Alter Epithelial Differentiationmentioning

confidence: 99%

Manipulation of Epithelial Differentiation by HPV Oncoproteins

White

2019

Viruses

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Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.

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Human papillomavirus E7 induces p63 expression to modulate DNA damage response

Cited by 18 publications

References 65 publications

Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis

Combined Transcriptome and Proteome Analysis of Immortalized Human Keratinocytes Expressing Human Papillomavirus 16 (HPV16) Oncogenes Reveals Novel Key Factors and Networks in HPV-Induced Carcinogenesis

Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation

Manipulation of Epithelial Differentiation by HPV Oncoproteins

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