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.
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.
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.
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.
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We thank Yixiang Wang of the Central Laboratory and Jianyun Zhang of the Department of pathology of Peking University School and Hospital of Stomatology for the assistances in various aspects of this work.
Ethics approval and consent to participate
For the study on the expression of G6PD in the samples of OSCC patients, it was approved by the Ethics Committee of Peking University School and Hospital of Stomatology (NO. PKUSSIRB-201944044) in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients, and telephone follow-up was performed to analyse the survival trends among these patients. For the animal study, all animal studies (including the mice euthanasia procedure) were done in compliance with the regulations and guidelines of Peking University institutional animal care and conducted according to the AAALAC and the IACUC guidelines (NO. LA2019011).
The data that support the findings of this study are available from the corresponding author upon reasonable request.
The authors declare no competing interests.
This study was supported by National Natural Science Foundation of China (81972540, 81672664, and 81802699), and the fund of Peking University School and Hospital of Stomatology (PKUSS20170206).
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Wang, Y., Li, Q., Niu, L. et al. Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-1007-3