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J Exp Clin Cancer Res. 2019 Feb 18;38(1):84. doi: 10.1186/s13046-019-1080-8.

Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis.

He L1,2, Gao L2,3, Shay C4, Lang L2, Lv F5, Teng Y6,7,8.

Author information

1
College of Bioengineering, Chongqing University, Chongqing, 400044, People's Republic of China.
2
Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, 30912, USA.
3
Chongqing University of Arts and Sciences, Chongqing, 402160, People's Republic of China.
4
Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
5
College of Bioengineering, Chongqing University, Chongqing, 400044, People's Republic of China. lyufenglin@cqu.edu.cn.
6
Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, 30912, USA. yteng@augusta.edu.
7
Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA. yteng@augusta.edu.
8
Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA, USA. yteng@augusta.edu.

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.

KEYWORDS:

Anticancer; Arf1; EGFR; HDAC; HNSCC; Invasion

PMID:
30777099
PMCID:
PMC6379952
DOI:
10.1186/s13046-019-1080-8
[Indexed for MEDLINE]
Free PMC Article

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