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

Abstract

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.

The Multiple Roles of Glucose-6-Phosphate Dehydrogenase in Tumorigenesis and Cancer Chemoresistance

“…It has been demonstrated that G6PD regulates many signaling pathways [65][66][67]. The study of Wang et al suggests that the inhibition of G6PD is associated with invasion, metastasis and EMT of oral squamous cell carcinoma (OSCC) through activating JNK, which enhances the E-Cadherin expression level and regulates MGAT3 expression transcriptionally to promote the bisecting GlcNAc-branched N-glycosylation of E-Cadherin [65] (Figure 6a).…”

Extracellular citrate and metabolic adaptations of cancer cells

“…However, G6PD silencing did moderately decrease lung colonisation when breast cancer cells were delivered through tail-vain injection [ 49 ]. A similar decrease of metastatic activity and no change of the primary tumour growth were observed when PPP activity was inhibited in melanoma [ 50 ], tongue cancer [ 51 ] or other oral squamous cell carcinomas [ 52 ].…”

“…However, G6PD silencing did moderately decrease lung colonisation when breast cancer cells were delivered through tail-vain injection [49]. A similar decrease of metastatic activity and no change of the primary tumour growth were observed when PPP activity was inhibited in melanoma [50], tongue cancer [51] or other oral squamous cell carcinomas [52]. K-Ras-driven tumours are known to rely heavily on glycolysis with increased glucose uptake, decreased Krebs cycle activity, increased glutamine use and reduced oxidative PPP [53,54].…”

FUT7 Promotes the Epithelial–Mesenchymal Transition and Immune Infiltration in Bladder Urothelial Carcinoma

“…Glycosylation, a key regulatory mechanism, is involved in kinds of cancer-related processes. 26,27 Abnormal glycosylation is a common phenomenon that has been observed in cancer, and it can determine cancer stage, grade, and the fate of cancer progression. [28][29][30] It is a contributor to the occurrence and development of cancers, including bladder cancer.…”