Abstract 4191
Background
Head and neck squamous carcinoma (HNSCC) accounts for more than 600,000 cases annually worldwide. Glycosylation is the most common post-translational modification of proteins, and aberrant glycosylation is a hallmark of cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) controls the crucial step in O-glycosylation and promotes malignant behavior in various cancers. However, its role in HNSCC remains unclear.
Methods
Immunohistochemistry was performed to analyze expression of C1GALT1 in 153 HNSCC tumors. Student t-test, Kaplan-Meier analysis, and Cox-regression analyses were used to analyze correlation of C1GALT1 expression with clinicopathological factors and survivals. CRISPR/Cas9 system was used to knock out C1GALT1. MTT assay, transwell migration, and Matrigel invasion assays were carried out to evaluate HNSCC cell viability, migration, and invasion, respectively. Human phospho-RTK array and Western blot analyses were performed to evaluate signaling pathways. ELISA was used to evaluate EGF-EGFR binding affinity. Mass spectrometry was used to identify O-glycopeptides on EGFR. Molecular docking simulation was used for searching C1GALT1 inhibitors. In vivo effects of C1GALT1 and its inhibitor were evaluated in NOD/SCID mice.
Results
C1GALT1 was overexpressed in HNSCC tumors and predicts poor survivals. C1GALT1 overexpression enhanced whereas C1GALT1 knockdown/knockout suppressed cell viability, migration, and invasion in HNSCC cells. Mechanistically, C1GALT1 modulated O-glycosylation of EGFR and enhanced EGF-EGFR binding affinity, leading to increased EGFR signaling and malignant phenotypes. Using mass spectrometry, we identified five O-glycopeptides on EGFR, among which four are within the ligand binding domain. Itraconazole, a C1GALT1 inhibitor, directly bound to C1GALT1 and changed O-glycans on cell surfaces and EGFR. Targeting C1GALT1 with CRISPR/Cas9, shRNA, or itraconazole was able to significantly suppress tumor growth in NOD/SCID mice.
Conclusions
Our findings indicate C1GALT1 as an attractive therapeutic target for HNSCC.
Clinical trial identification
Legal entity responsible for the study
National Taiwan University Hospital.
Funding
Ministry of Science and Technology National Taiwan University Hospital, Hsinchu branch.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1159 - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome
Presenter: Elisenda Llabres Valenti
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3725 - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3708 - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5057 - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer
Presenter: Soodabeh Shahid Sales
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5970 - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR
Presenter: KARISHMA BAKSHI
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1360 - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma
Presenter: Hanhee Jo
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1634 - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System
Presenter: Yang Ge
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4921 - Measuring the Efficiency of Cancer Care in Europe
Presenter: Rikard Althin
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1235 - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients
Presenter: Chih-Yung Yang
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5169 - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.
Presenter: Natalia Levitskaya
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract