title: N-glycosylation induces the CTHRC1 protein and drives oral cancer cell migration.
abstract: Oral squamous cell carcinoma (OSCC) is one of the most pernicious malignancies, but the mechanisms underlying its development and progression are poorly understood. One of the key pathways implicated in OSCC is the canonical Wnt/β-catenin signaling pathway. Previously, we reported that canonical Wnt signaling functions in a positive feedback loop with the DPAGT1 gene, a principal regulator of the metabolic pathway of protein N-glycosylation, to hyperglycosylate E-cadherin and reduce intercellular adhesion. Here, we show that in OSCC, DPAGT1 and canonical Wnt signaling converge to up-regulate CTHRC1 (collagen triple helix repeat containing 1), an N-glycoprotein implicated in tumor invasion and metastasis. We found that in human OSCC specimens, amplification of the levels of CTHRC1 was associated with its hyperglycosylation. Partial inhibition of DPAGT1 expression in OSCC CAL27 cells reduced CTHRC1 abundance by increasing protein turnover, indicating that N-glycosylation stabilizes CTHRC1. Additionally, canonical Wnt signaling promoted β-catenin/T-cell factor transcriptional activity at the CTHRC1 promoter to further elevate CTHRC1 levels. We demonstrate that DPAGT1 promotes cell migration and drives the localization of CTHRC1 to cells at the leading edge of a wound front coincident with drastic changes in cell morphology. We propose that in OSCC, dysregulation of canonical Wnt signaling and DPAGT1-dependent N-glycosylation induces CTHRC1, thereby driving OSCC cell migration and tumor spread.
authors.affiliation: School of Stomatology, Shandong University, Shandong 250100, China.
authors.forename: Gangli
authors.initials: G
authors.lastname: Liu
authors.forename: Pritam K
authors.initials: PK
authors.lastname: Sengupta
authors.forename: Basem
authors.initials: B
authors.lastname: Jamal
authors.forename: Hsiao-Ying
authors.initials: HY
authors.lastname: Yang
authors.forename: Meghan P
authors.initials: MP
authors.lastname: Bouchie
authors.forename: Volkhard
authors.initials: V
authors.lastname: Lindner
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.forename: Maria A
authors.initials: MA
authors.lastname: Kukuruzinska
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D017855:Transferases (Other Substituted Phosphate Groups); C023222:UDPacetylglucosamine-dolichyl-phosphate acetylglucosamine-1-phosphate transferase
keywords: CTHRC1; Cancer; Canonical Wnt; Cell Migration; DPAGT1; Glycoprotein; Glycosylation; OSCC; Wnt Signaling