p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma
The complex heterogeneity of head and neck squamous cell carcinoma (HNSCC) reflects a diverse underlying etiology. This heterogeneity is also apparent within Human Papillomavirus-positive (HPV+) HNSCC subtypes, which have distinct gene expression profiles and patient outcomes. One aggressive HPV+ HN...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.879054/full |
| _version_ | 1818213906277990400 |
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| author | Alexandra Ruth Glathar Akinsola Oyelakin Christian Gluck Jonathan Bard Satrajit Sinha |
| author_facet | Alexandra Ruth Glathar Akinsola Oyelakin Christian Gluck Jonathan Bard Satrajit Sinha |
| author_sort | Alexandra Ruth Glathar |
| collection | DOAJ |
| description | The complex heterogeneity of head and neck squamous cell carcinoma (HNSCC) reflects a diverse underlying etiology. This heterogeneity is also apparent within Human Papillomavirus-positive (HPV+) HNSCC subtypes, which have distinct gene expression profiles and patient outcomes. One aggressive HPV+ HNSCC subtype is characterized by elevated expression of genes involved in keratinization, a process regulated by the oncogenic transcription factor ΔNp63. Furthermore, the human TP63 gene locus is a frequent HPV integration site and HPV oncoproteins drive ΔNp63 expression, suggesting an unexplored functional link between ΔNp63 and HPV+ HNSCC. Here we show that HPV+ HNSCCs can be molecularly stratified according to ΔNp63 expression levels and derive a ΔNp63-associated gene signature profile for such tumors. We leveraged RNA-seq data from p63 knockdown cells and ChIP-seq data for p63 and histone marks from two ΔNp63high HPV+ HNSCC cell lines to identify an epigenetically refined ΔNp63 cistrome. Our integrated analyses reveal crucial ΔNp63-bound super-enhancers likely to mediate HPV+ HNSCC subtype-specific gene expression that is anchored, in part, by the PI3K-mTOR pathway. These findings implicate ΔNp63 as a key regulator of essential oncogenic pathways in a subtype of HPV+ HNSCC that can be exploited as a biomarker for patient stratification and treatment choices. |
| first_indexed | 2024-12-12T06:11:44Z |
| format | Article |
| id | doaj.art-97a42fa3b1d541898f7d3b727d6e563e |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T06:11:44Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-97a42fa3b1d541898f7d3b727d6e563e2022-12-22T00:35:09ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.879054879054p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell CarcinomaAlexandra Ruth GlatharAkinsola OyelakinChristian GluckJonathan BardSatrajit SinhaThe complex heterogeneity of head and neck squamous cell carcinoma (HNSCC) reflects a diverse underlying etiology. This heterogeneity is also apparent within Human Papillomavirus-positive (HPV+) HNSCC subtypes, which have distinct gene expression profiles and patient outcomes. One aggressive HPV+ HNSCC subtype is characterized by elevated expression of genes involved in keratinization, a process regulated by the oncogenic transcription factor ΔNp63. Furthermore, the human TP63 gene locus is a frequent HPV integration site and HPV oncoproteins drive ΔNp63 expression, suggesting an unexplored functional link between ΔNp63 and HPV+ HNSCC. Here we show that HPV+ HNSCCs can be molecularly stratified according to ΔNp63 expression levels and derive a ΔNp63-associated gene signature profile for such tumors. We leveraged RNA-seq data from p63 knockdown cells and ChIP-seq data for p63 and histone marks from two ΔNp63high HPV+ HNSCC cell lines to identify an epigenetically refined ΔNp63 cistrome. Our integrated analyses reveal crucial ΔNp63-bound super-enhancers likely to mediate HPV+ HNSCC subtype-specific gene expression that is anchored, in part, by the PI3K-mTOR pathway. These findings implicate ΔNp63 as a key regulator of essential oncogenic pathways in a subtype of HPV+ HNSCC that can be exploited as a biomarker for patient stratification and treatment choices.https://www.frontiersin.org/articles/10.3389/fonc.2022.879054/fullp63HPVHNSCCgene expression profilingbiomarker |
| spellingShingle | Alexandra Ruth Glathar Akinsola Oyelakin Christian Gluck Jonathan Bard Satrajit Sinha p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma Frontiers in Oncology p63 HPV HNSCC gene expression profiling biomarker |
| title | p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma |
| title_full | p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma |
| title_fullStr | p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma |
| title_full_unstemmed | p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma |
| title_short | p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma |
| title_sort | p63 directs subtype specific gene expression in hpv head and neck squamous cell carcinoma |
| topic | p63 HPV HNSCC gene expression profiling biomarker |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.879054/full |
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