Human Papilloma Virus Increases ΔNp63α Expression in Head and Neck Squamous Cell Carcinoma

Citro, Simona; Bellini, Alice; Medda, Alessandro; Sabatini, Maria Elisa; Tagliabue, Marta; Chu, Francesco; Chiocca, Susanna

doi:10.3389/fcimb.2020.00143

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…We stratified the data according to the levels of NF-Y subunits (top 25% versus lowest 75%): NF-YA total and NF-YAl were not significant, but NF-YAs correlated with a better prognosis ( Figure 6 E, left panel). As positive controls, we evaluated CDKN2A, whose high levels are known to be protective [ 6 ], as well as ΔNp63, which we recently demonstrated to be increased in HPV-positive by the E6 viral protein [ 47 ]; both genes are indeed very significantly protective ( Figure 6 E, middle and right panels). Finally, pairwise combination of curves of NF-YAs with CDKN2A or ΔNp63 further confirmed this point ( Figure 6 F).…”

Section: Resultsmentioning

confidence: 99%

NF-Y Subunits Overexpression in HNSCC

Bezzecchi

Bernardini

Ronzio

et al. 2021

Cancers

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NF-Y is the CCAAT-binding trimer formed by the histone fold domain (HFD), NF-YB/NF-YC and NF-YA. The CCAAT box is generally prevalent in promoters of “cancer” genes. We reported the overexpression of NF-YA in BRCA, LUAD and LUSC, and of all subunits in HCC. Altered splicing of NF-YA was found in breast and lung cancer. We analyzed RNA-seq datasets of TCGA and cell lines of head and neck squamous cell carcinomas (HNSCC). We partitioned all TCGA data into four subtypes, deconvoluted single-cell RNA-seq of tumors and derived survival curves. The CCAAT box was enriched in the promoters of overexpressed genes. The “short” NF-YAs was overexpressed in all subtypes and the “long” NF-YAl in Mesenchymal. The HFD subunits are overexpressed, except Basal (NF-YB) and Atypical (NF-YC); NF-YAl is increased in p53 mutated tumors. In HPV-positive tumors, high levels of NF-YAs, p16 and ΔNp63 correlate with better prognosis. Deconvolution of single cell RNA-seq (scRNA-seq) found a correlation of NF-YAl with Cancer Associated Fibroblasts (CAFs) and p-EMT cells, a population endowed with metastatic potential. We conclude that overexpression of HFD subunits and NF-YAs is protective in HPV-positive tumors; expression of NF-YAl is largely confined to mutp53 tumors and malignant p-EMT cells.

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Section: Resultsmentioning

confidence: 99%

NF-Y Subunits Overexpression in HNSCC

Bezzecchi

Bernardini

Ronzio

et al. 2021

Cancers

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“…P53 transcription factor family, including p53 (TP53), p63 (TP63) and p73 (TP73), is a key player in tumor development and formation. p63 is expressed by two different promoters, resulting in two isoforms (TAp63 and DNp63) with or without amino (N) terminal transactivation domain that is necessary to induce apoptosis and tumor inhibition [ 8 , 9 ]. Alternative splicing of the 3′ end of ΔNp63 mRNA produces α, β and γ subtype [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC

Tian

Zhang

et al. 2021

Cancer Cell Int

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Background Head and neck squamous cell carcinoma (HNSCC) are one of the most common types of head and neck cancer, and it is urgent to find effective treatment for advanced patients. Exploring developing and progressing mechanisms of HNSCC could provide a theoretical basis to find new therapeutic targets. Methods In our research, we performed a whole-gene expression profile microarray analysis to identify differential expression genes between squamous cell carcinoma cells and ΔNp63 alpha (ΔNp63α) knockdown cells. As a result, an important gene Synaptotagmin VII (SYT7) was screened out. Results SYT7 knockdown affected the proliferation, apoptosis and cell cycle of squamous cell carcinoma cells. The rescue experiment in vitro with ΔNp63α and SYT7 double knockdown resulted in partial reversion of ΔNp63α-induced phenotypes. This was also confirmed by experiments in vivo. Conclusions Taken together, we found that ΔNp63α could inhibit the occurrence and progression of HNSCC throughout downregulating the expression of SYT7. Therefore, SYT7/ΔNp63α axis could be a potential therapeutic target for clinical treatment of HNSCC.

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“…As shown in Fig. 2E, also in HPV-positive HNC cell lines ΔNp63α knock-down strongly reduces SMAD4 expression, suggesting that UMSCC47 has lower levels of SMAD4 compared to the other HPV-positive HNC cell lines due to the lack of ΔNp63α, whose expression is also regulated by HPV16 [19]. Since p53 silencing has been shown to increase SMAD4 expression in breast cancer cell lines [29], we hypothesise a possible role of p53, which is downregulated in the presence of E6, in the regulation of SMAD4.…”

Section: Hpv16 Regulates Smad4 Protein Levelmentioning

confidence: 74%

“…HNC cell lines, acquired from different sources [17], were accurately described and cited in our previous studies [18,19]. Cells were grown in Dulbecco's modified Eagle's medium (Euroclone) supplemented with antibiotics, 2 mM L-glutamine, 10% FBS (Fisher Scientific) and non-essential amino-acids (NEAA).…”

Section: Cell Culturementioning

confidence: 99%

HPV-mediated regulation of SMAD4 modulates the DNA damage response in head and neck cancer

Citro

Miccolo

Medda

et al. 2022

J Exp Clin Cancer Res

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Background Head and Neck cancer (HNC) is a fatal malignancy with poor prognosis. Human Papillomavirus (HPV) infection is becoming the prominent cause of HNC in the western world, and studying the molecular mechanisms underlying its action in cancers is key towards targeted therapy. To replicate, HPV regulates the host DNA damage repair (DDR) pathway. SMAD4 is also involved in the regulation of the DDR machinery and likely plays important role in maintaining cell viability upon genotoxic stress. In this study, we investigated the role of HPV in the upregulation of SMAD4 to control the DDR response and facilitate its lifecycle. Methods SMAD4, Rad51 and CHK1 expression was assessed in HPV-positive and HPV-negative HNC using TCGA data, a panel of 14 HNC cell lines and 8 fresh tumour tissue samples from HNC patients. HPV16 expression was modulated by E6/E7 siRNA knock-down or transduction in HPV-positive HNC cell lines and Human Primary keratinocytes respectively. SMAD4 half-life was assessed by cycloheximide treatment in HNC cell lines, together with βTRCP1-dependent SMAD4 ubiquitination. SMAD4 siRNA knock-down was used to determine its role in HPV-mediated regulation of DDR machinery and to assess cisplatin sensitivity in HPV-positive HNC cell lines. Results We found that HPV increases SMAD4 expression is both HPV-positive HNC tumours and cell lines, impairing its degradation which is mediated by the E3 ubiquitin ligase βTRCP1. SMAD4 expression highly correlates with the expression of two main players of the DDR pathway, CHK1 and Rad51, which expression is also upregulated by the presence of HPV. In particular, we demonstrate that HPV stabilizes SMAD4 to increase CHK1 and Rad51 expression. In addition, SMAD4-deficient HPV-positive cells have increased sensitivity to cisplatin treatment. Conclusions Our results give a clear molecular mechanism at the basis of HPV regulation of the DDR pathway. In particular, we show how HPV stabilizes SMAD4 to promote DDR protein expression, which may be used to facilitate viral replication and HNC onset. Moreover, we found that SMAD4 silencing in HPV-positive HNC cell lines increases sensitivity to cisplatin treatment, suggesting that HPV-positive HNC with low SMAD4 expression may be preferentially susceptible to similar treatments.

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Human Papilloma Virus Increases ΔNp63α Expression in Head and Neck Squamous Cell Carcinoma

Cited by 11 publications

References 30 publications

NF-Y Subunits Overexpression in HNSCC

NF-Y Subunits Overexpression in HNSCC

SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC

HPV-mediated regulation of SMAD4 modulates the DNA damage response in head and neck cancer

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