β-catenin/CBP Inhibition Alters Epidermal Growth Factor Receptor Fucosylation Status in Oral Squamous Cell Carcinoma.

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EGFR is a glycoprotein receptor tyrosine kinase (RTK) whose activity is upregulated in >80 % OSCC. Current anti-EGFR therapy relies on the use of cetuximab, a monoclonal antibody against EGFR, although it has had only a limited response in patients. Here, we uncover a novel mechanism regulating EGFR activity, identifying a role of the nuclear branch of the Wnt/β-catenin signaling pathway, the β-catenin/CBP axis, in control of EGFR posttranslational modification with N-glycans. Genomic and structural analyses reveal that β-catenin/CBP signaling represses fucosylation on the antennae of N-linked glycans on EGFR. By employing nUPLC-MS/MS, we determined that malignant human OSCC cells harbor EGFR with a paucity of N-glycan antennary fucosylation, while indolent cells display higher levels of fucosylation at sites N420 and N579. Additionally, treatment with either ICG-001 or E7386, which are both small molecule inhibitors of β-catenin/CBP signaling, leads to increased transcriptional expression of fucosyltransferases FUT2 and FUT3, with a concomitant increase in EGFR N-glycan antennary fucosylation. In order to discover which fucosylated glycan epitopes are involved in the observed effect, we performed in-depth characterization of multiply-fucosylated N-glycans via glycopeptide tandem mass spectrometry of the EGFR tryptic glycopeptides. Data are available via ProteomeXchange with identifier PXD017060. We propose that β-catenin/CBP signaling promotes EGFR oncogenic activity in OSCC by inhibiting its N-glycan antennary fucosylation through transcriptional repression of FUT2 and FUT3.", "claims": [{"id": "claim-data-access", "statement": "Peptide, glycopeptide and formerly-N-glycosylated peptide mass spectrometry data have been deposited to the ProteomeXchange Consortium (61) via the PRIDE (62) partner repository with the dataset identifier PXD017060, in compliance with MIRAGE standards (63).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:32203567", "locator": "sections[23] \"fn-group\" paragraph 1", "quote": "Peptide, glycopeptide and formerly-N-glycosylated peptide mass spectrometry data have been deposited to the ProteomeXchange Consortium (61) via the PRIDE (62) partner repository with the dataset identifier PXD017060, in compliance with MIRAGE standards (63)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The proportional abundance of this glycan composition increased from 6.4 +/− 2.1% in the control to 18.5 +/− 0.5% after treatment with ICG-001 (Fig. 4A, Supplementary Table 8) (p=1.3 × 10−3).", "kind": "quantitative", "target": {"value": 1.3, "unit": "p-value", "tolerance": null, "source": "The proportional abundance of this glycan composition increased from 6.4 +/− 2.1% in the control to 18.5 +/− 0.5% after treatment with ICG-001 (Fig. 4A, Supplementary Table 8) (p=1.3 × 10−3)."}, "evidence": [{"asset": "source:pmid:32203567", "locator": "sections[6] \"Inhibition of β-catenin-CBP Signaling in Metastatic HSC-3 Cells Results in Increased Fucosylation of EGFR N-Glycans.\" paragraph 2", "quote": "The proportional abundance of this glycan composition increased from 6.4 +/− 2.1% in the control to 18.5 +/− 0.5% after treatment with ICG-001 (Fig. 4A, Supplementary Table 8) (p=1.3 × 10−3)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The proportional abundance of this glycan composition increased from 6.4 +/− 2.1% in the control to 18.5 +/− 0.5% after treatment with ICG-001 (Fig. 4A, Supplementary Table 8) (p=1.3 × 10−3).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:32203567"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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