High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma
Abstract Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Among the oncogenes at this locus, CCND1 and ANO1 are linked to poor prognosis; however, their individual roles in treatment resistance remain unclear. The impact of Cyclin...
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Nature Portfolio
2025-01-01
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| author | Solenne Bourdier Anne-Sophie Fisch Keziban Merve Alp Ridhima Das Philipp Mertins Ingeborg Tinhofer |
| author_facet | Solenne Bourdier Anne-Sophie Fisch Keziban Merve Alp Ridhima Das Philipp Mertins Ingeborg Tinhofer |
| author_sort | Solenne Bourdier |
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| description | Abstract Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Among the oncogenes at this locus, CCND1 and ANO1 are linked to poor prognosis; however, their individual roles in treatment resistance remain unclear. The impact of Cyclin D1 and Ano1 overexpression on survival was analyzed using the TCGA HNSCC dataset and a Charité cohort treated with cisplatin (CDDP)-based radiochemotherapy. High Ano1 expression was primarily associated with poor overall survival in both datasets. The effects of CCND1 and ANO1 knockdown (KD) on radio- and drug sensitivity, along with changes in global protein expression, cell viability, growth, and DNA repair, were studied in an 11q13-amplified HNSCC cell line model of primary cisplatin resistance. Unique pathway alterations– VEGF in CCND1 KD and the Rho GTPase cycle in ANO1 KD– were observed, along with shared changes like DNA damage and cell cycle dysregulation. Silencing CCND1 or ANO1 increased CDDP sensitivity, while only ANO1 silencing increased radiosensitivity. Copanlisib and afatinib were identified as promising candidates for combination therapy of 11q13-amplified HNSCC tumors. We demonstrated a predominant role for Ano1 in treatment resistance in Cyclin D1highAno1high HNSCC tumors and identified novel potential treatment combinations for this high-risk patient group. |
| format | Article |
| id | doaj-art-274c5fab7ca94a548522e92423036361 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-274c5fab7ca94a548522e924230363612025-01-12T12:14:35ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-025-85214-9High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinomaSolenne Bourdier0Anne-Sophie Fisch1Keziban Merve Alp2Ridhima Das3Philipp Mertins4Ingeborg Tinhofer5Department of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinDepartment of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinMax Delbrück Center for Molecular MedicineDepartment of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinMax Delbrück Center for Molecular MedicineDepartment of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu BerlinAbstract Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Among the oncogenes at this locus, CCND1 and ANO1 are linked to poor prognosis; however, their individual roles in treatment resistance remain unclear. The impact of Cyclin D1 and Ano1 overexpression on survival was analyzed using the TCGA HNSCC dataset and a Charité cohort treated with cisplatin (CDDP)-based radiochemotherapy. High Ano1 expression was primarily associated with poor overall survival in both datasets. The effects of CCND1 and ANO1 knockdown (KD) on radio- and drug sensitivity, along with changes in global protein expression, cell viability, growth, and DNA repair, were studied in an 11q13-amplified HNSCC cell line model of primary cisplatin resistance. Unique pathway alterations– VEGF in CCND1 KD and the Rho GTPase cycle in ANO1 KD– were observed, along with shared changes like DNA damage and cell cycle dysregulation. Silencing CCND1 or ANO1 increased CDDP sensitivity, while only ANO1 silencing increased radiosensitivity. Copanlisib and afatinib were identified as promising candidates for combination therapy of 11q13-amplified HNSCC tumors. We demonstrated a predominant role for Ano1 in treatment resistance in Cyclin D1highAno1high HNSCC tumors and identified novel potential treatment combinations for this high-risk patient group.https://doi.org/10.1038/s41598-025-85214-9HNSCC11q13 amplificationAnoctamin-1TMEM16ARadiosensitivityMass spectrometry |
| spellingShingle | Solenne Bourdier Anne-Sophie Fisch Keziban Merve Alp Ridhima Das Philipp Mertins Ingeborg Tinhofer High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma Scientific Reports HNSCC 11q13 amplification Anoctamin-1 TMEM16A Radiosensitivity Mass spectrometry |
| title | High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma |
| title_full | High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma |
| title_fullStr | High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma |
| title_full_unstemmed | High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma |
| title_short | High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma |
| title_sort | high ano1 expression as key driver of resistance to radiation and cisplatin in hpv negative head and neck squamous cell carcinoma |
| topic | HNSCC 11q13 amplification Anoctamin-1 TMEM16A Radiosensitivity Mass spectrometry |
| url | https://doi.org/10.1038/s41598-025-85214-9 |
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