C1GALT1 predicts poor prognosis and is a potential therapeutic target in head and neck cancer
Journal
Oncogene
Journal Volume
37
Journal Issue
43
Pages
5780-5793
Date Issued
2018
Author(s)
Abstract
Core 1 β1,3-galactosyltransferase (C1GALT1) controls the crucial step of GalNAc-type O-glycosylation and is overexpressed in various human malignancies. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here we demonstrate that C1GALT1 expression is upregulated in HNSCC tumors and is associated with adverse clinicopathologic features. Moreover, high C1GALT1 expression predicts poor disease-free and overall survivals. C1GALT1 overexpression enhances HNSCC cell viability, migration, and invasion, which can be reversed by erlotinib. Silencing of C1GALT1 suppresses the malignant behavior both in vitro and in vivo. Mass spectrometry and lectin pull-down assays demonstrate that C1GALT1 modifies O-glycans on EGFR. Blocking O-glycan elongation on EGFR by C1GALT1 knockdown decreases EGF-EGFR binding affinity and inhibits EGFR signaling, thereby suppressing malignant phenotypes. Using molecular docking simulations, we identify itraconazole as a C1GALT1 inhibitor that directly binds C1GALT1 and promotes its proteasomal degradation, leading to significant blockade of C1GALT1-mediated effects in HNSCC cells in vitro and in vivo. Collectively, our findings demonstrate a critical role of O-glycosylation in HNSCC progression and highlight the therapeutic potential of targeting C1GALT1 in HNSCC treatment. ? 2018, The Author(s).
Other Subjects
core 1 beta1,3 galactosyltransferase; epidermal growth factor; epidermal growth factor receptor; erlotinib; galactosyltransferase; glycan derivative; itraconazole; lectin; unclassified drug; C1GALT1 protein, human; EGFR protein, human; epidermal growth factor receptor; galactosyltransferase; itraconazole; tumor protein; animal experiment; animal model; animal tissue; antineoplastic activity; Article; binding affinity; cancer inhibition; cancer prognosis; cancer survival; cell invasion; cell migration; cell viability; clinical feature; controlled study; disease free survival; drug targeting; female; gene knockdown; gene overexpression; gene silencing; glycosylation; head and neck squamous cell carcinoma; head and neck squamous cell carcinoma cell line; human; human tissue; in vitro study; in vivo study; mass spectrometry; molecular docking; mouse; nonhuman; overall survival; pharmacological blocking; phenotype; prediction; priority journal; protein degradation; protein function; protein phosphorylation; receptor binding; signal transduction; upregulation; antagonists and inhibitors; biosynthesis; cell motion; cell survival; chemistry; drug effect; enzymology; gene expression regulation; genetics; head and neck tumor; male; metabolism; molecular docking; pathology; predictive value; prognosis; tumor cell line; tumor invasion; Cell Line, Tumor; Cell Movement; Cell Survival; ErbB Receptors; Female; Galactosyltransferases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glycosylation; Head and Neck Neoplasms; Humans; Itraconazole; Male; Molecular Docking Simulation; Neoplasm Invasiveness; Neoplasm Proteins; Predictive Value of Tests; Prognosis
Publisher
Nature Publishing Group
Type
journal article