Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis
Abstract Background A promising arsenal of histone deacetylase (HDAC)-targeted treatment has emerged in the past decade, as the abnormal targeting or retention of HDACs to DNA regulatory regions often occurs in many cancers. Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive...
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1080-8 |
| _version_ | 1818837722119274496 |
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| author | Leilei He Lixia Gao Chloe Shay Liwei Lang Fenglin Lv Yong Teng |
| author_facet | Leilei He Lixia Gao Chloe Shay Liwei Lang Fenglin Lv Yong Teng |
| author_sort | Leilei He |
| collection | DOAJ |
| description | Abstract Background A promising arsenal of histone deacetylase (HDAC)-targeted treatment has emerged in the past decade, as the abnormal targeting or retention of HDACs to DNA regulatory regions often occurs in many cancers. Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies worldwide associated with poor overall survival in late-stage patients. HDAC inhibitors have great potential to treat this devastating disease; however, few has been studied regarding the beneficial role of HDAC inhibition in anti-HNSCC therapy and the underlying molecular mechanisms remain elusive. Methods Cell migration and invasion were examined by wound closure and Transwell assays. Protein levels and interactions were assessed by Western blotting and immunoprecipitation. HDAC activity was measured with the fluorometric HDAC Activity Assay. Phospho-receptor tyrosine kinase (RTK) profiling was determined by the Proteome Profiler Human Phospho-RTK Array. Results ADP-ribosylation factor 1 (Arf1), a small GTPase coordinating vesicle-mediated intracellular trafficking, can be inactivated by HDAC inhibitors through histone acetylation-independent degradation of epidermal growth factor receptor (EGFR) in HNSCC cells. Mechanistically, high levels of Arf1 activity are maintained by binding to phosphorylated EGFR which is localized on HNSCC cell plasma membrane. Decreased EGFR phosphorylation is associated with reduced EGFR protein levels in the presence of TSA, which inactivates Arf1 and eventually inhibits invasion in HNSCC cells. Conclusions Our insights explore the critical role of EGFR-Arf1 complex in driving HNSCC progression, and demonstrate the selective action of HDAC inhibitors on this specific axis for suppressing HNSCC invasion. This novel finding represents the first example of modulating the EGFR-Arf1 complex in HNSCC by small molecule agents. |
| first_indexed | 2024-12-19T03:27:01Z |
| format | Article |
| id | doaj.art-2433af4f091e4183a430ad123b3e3e51 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-19T03:27:01Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-2433af4f091e4183a430ad123b3e3e512022-12-21T20:37:35ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-02-0138111010.1186/s13046-019-1080-8Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axisLeilei He0Lixia Gao1Chloe Shay2Liwei Lang3Fenglin Lv4Yong Teng5College of Bioengineering, Chongqing UniversityDepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta UniversityDepartment of Pediatrics, School of Medicine, Emory UniversityDepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta UniversityCollege of Bioengineering, Chongqing UniversityDepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta UniversityAbstract Background A promising arsenal of histone deacetylase (HDAC)-targeted treatment has emerged in the past decade, as the abnormal targeting or retention of HDACs to DNA regulatory regions often occurs in many cancers. Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies worldwide associated with poor overall survival in late-stage patients. HDAC inhibitors have great potential to treat this devastating disease; however, few has been studied regarding the beneficial role of HDAC inhibition in anti-HNSCC therapy and the underlying molecular mechanisms remain elusive. Methods Cell migration and invasion were examined by wound closure and Transwell assays. Protein levels and interactions were assessed by Western blotting and immunoprecipitation. HDAC activity was measured with the fluorometric HDAC Activity Assay. Phospho-receptor tyrosine kinase (RTK) profiling was determined by the Proteome Profiler Human Phospho-RTK Array. Results ADP-ribosylation factor 1 (Arf1), a small GTPase coordinating vesicle-mediated intracellular trafficking, can be inactivated by HDAC inhibitors through histone acetylation-independent degradation of epidermal growth factor receptor (EGFR) in HNSCC cells. Mechanistically, high levels of Arf1 activity are maintained by binding to phosphorylated EGFR which is localized on HNSCC cell plasma membrane. Decreased EGFR phosphorylation is associated with reduced EGFR protein levels in the presence of TSA, which inactivates Arf1 and eventually inhibits invasion in HNSCC cells. Conclusions Our insights explore the critical role of EGFR-Arf1 complex in driving HNSCC progression, and demonstrate the selective action of HDAC inhibitors on this specific axis for suppressing HNSCC invasion. This novel finding represents the first example of modulating the EGFR-Arf1 complex in HNSCC by small molecule agents.http://link.springer.com/article/10.1186/s13046-019-1080-8HDACArf1EGFRHNSCCInvasionAnticancer |
| spellingShingle | Leilei He Lixia Gao Chloe Shay Liwei Lang Fenglin Lv Yong Teng Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis Journal of Experimental & Clinical Cancer Research HDAC Arf1 EGFR HNSCC Invasion Anticancer |
| title | Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis |
| title_full | Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis |
| title_fullStr | Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis |
| title_full_unstemmed | Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis |
| title_short | Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis |
| title_sort | histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation independent blockade of the egfr arf1 axis |
| topic | HDAC Arf1 EGFR HNSCC Invasion Anticancer |
| url | http://link.springer.com/article/10.1186/s13046-019-1080-8 |
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