Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis

• Published in: British journal of cancer 2020-10, Vol.123 (8), p.1315-1325
• Main Authors: Wang, Yifei, Li, Qingxiang, Niu, Lixuan, Xu, Le, Guo, Yuxing, Wang, Lin, Guo, Chuanbin
• Format: Article
• Language: English
• Subjects: 631/337/458/1524; 631/67/1665; 631/67/2327; 631/67/322; 631/80/79/1902; Acetylglucosamine - metabolism; AKT protein; Animals; Biomedical and Life Sciences; Biomedicine; Cadherins - metabolism; Cancer Research; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Dehydroepiandrosterone; Drug Resistance; E-cadherin; Epidemiology; Epithelial-Mesenchymal Transition - physiology; Female; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - antagonists & inhibitors; Glucosephosphate Dehydrogenase - physiology; Glycogen Synthase Kinase 3 beta - physiology; Glycosylation; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - physiology; Lymphatic Metastasis; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Molecular Medicine; Mouth Neoplasms - metabolism; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Oncology; Oral cancer; Oral squamous cell carcinoma; Pentose phosphate pathway; Proto-Oncogene Proteins c-akt - physiology; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - mortality; Squamous Cell Carcinoma of Head and Neck - pathology; Transcription; Tumors; Wound healing; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-1007-3

Background As the rate-limit enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD) plays important roles in tumour progression, but the exact mechanism through which G6PD controls cancer metastasis remains unclear. Methods G6PD expression in resected oral squamous cell carcinoma (OSCC) samples was analysed by immunohistochemistry. The effects and mechanism of G6PD suppression on OSCC cell lines were measured by transwell assay, wound healing assay, western and lectin blot, mass spectrometer analysis, ChIP-PCR, and luciferase reporter assay. BALB/c-nude mice were used to establish orthotopic xenograft model. Results G6PD expression in the tumours of 105 OSCC patients was associated with lymphatic metastasis and prognosis. In vitro cellular study suggested that G6PD suppression impaired cell migration, invasion, and epithelial-mesenchymal transition. Furtherly, G6PD knockdown activated the JNK pathway, which then blocked the AKT/GSK-3β/Snail axis to induce E-Cadherin expression and transcriptionally regulated MGAT3 expression to promote bisecting GlcNAc-branched N-glycosylation of E-Cadherin. An orthotopic xenograft model further confirmed that dehydroepiandrosterone reduced lymphatic metastatic rate of OSCC, which was partially reversed by JNK inhibition. Conclusions Suppression of G6PD promoted the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin via activating the JNK pathway, which thus acted on OSCC metastasis.