ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease t...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/1170 |
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| author | Artemis Filippou Henna Pehkonen Piia-Riitta Karhemo Juho Väänänen Anni I. Nieminen Juha Klefström Reidar Grénman Antti A. Mäkitie Heikki Joensuu Outi Monni |
| author_facet | Artemis Filippou Henna Pehkonen Piia-Riitta Karhemo Juho Väänänen Anni I. Nieminen Juha Klefström Reidar Grénman Antti A. Mäkitie Heikki Joensuu Outi Monni |
| author_sort | Artemis Filippou |
| collection | DOAJ |
| description | Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (<i>ANO1</i>) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27<sup>Kip1</sup> expression. Suppressing ANO1 expression led to redistribution of p27<sup>Kip1</sup> from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target. |
| first_indexed | 2024-03-10T13:25:08Z |
| format | Article |
| id | doaj.art-6d0fcf088c224111a69fb308508676ba |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:25:08Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6d0fcf088c224111a69fb308508676ba2023-11-21T09:44:01ZengMDPI AGCancers2072-66942021-03-01135117010.3390/cancers13051170ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell CarcinomaArtemis Filippou0Henna Pehkonen1Piia-Riitta Karhemo2Juho Väänänen3Anni I. Nieminen4Juha Klefström5Reidar Grénman6Antti A. Mäkitie7Heikki Joensuu8Outi Monni9Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandTranslational Cancer Medicine Research Program and Medicum, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandFinnish Cancer Institute, FICAN South Helsinki University Hospital, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandDepartment of Otorhinolaryngology-Head and Neck Surgery, University of Turku and Turku University Hospital, 20520 Turku, FinlandDepartment of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, 00130 Helsinki, FinlandDepartment of Oncology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, FinlandApplied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, FinlandHead and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (<i>ANO1</i>) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27<sup>Kip1</sup> expression. Suppressing ANO1 expression led to redistribution of p27<sup>Kip1</sup> from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target.https://www.mdpi.com/2072-6694/13/5/1170ANO1head and neck cancerp27<sup>Kip1</sup>MCL1intrinsic apoptosiscell cycle |
| spellingShingle | Artemis Filippou Henna Pehkonen Piia-Riitta Karhemo Juho Väänänen Anni I. Nieminen Juha Klefström Reidar Grénman Antti A. Mäkitie Heikki Joensuu Outi Monni ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma Cancers ANO1 head and neck cancer p27<sup>Kip1</sup> MCL1 intrinsic apoptosis cell cycle |
| title | ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma |
| title_full | ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma |
| title_fullStr | ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma |
| title_full_unstemmed | ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma |
| title_short | ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma |
| title_sort | ano1 expression orchestrates p27kip1 mcl1 mediated signaling in head and neck squamous cell carcinoma |
| topic | ANO1 head and neck cancer p27<sup>Kip1</sup> MCL1 intrinsic apoptosis cell cycle |
| url | https://www.mdpi.com/2072-6694/13/5/1170 |
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