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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

4191 - C1GALT1 predicts poor prognosis and is a potential therapeutic target in head and neck cancer

Date

21 Oct 2018

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

Topics

Tumour Site

Head and Neck Cancers

Presenters

Mei-Chun Lin

Citation

Annals of Oncology (2018) 29 (suppl_8): viii372-viii399. 10.1093/annonc/mdy287

Authors

M. Lin1, P. Chien1, H. Wu2, S. Chen3, H. Juan4, N. Lin3, P. Lou1, M. Huang3

Author affiliations

  • 1 Otolaryngology, National Taiwan University Hospital, 100 - Taipei/TW
  • 2 Instrumentation Center, National Taiwan University, 100 - Taipei/TW
  • 3 Graduate Institute Of Anatomy And Cell Biology,, National Taiwan University, 100 - Taipei/TW
  • 4 Department Of Life Science, Graduate Institute Of Biomedical Electronics And Bioinformatics, National Taiwan University, 100 - Taipei/TW
More

Resources

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.

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