Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis.
Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis.
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抑制 G6PD 会诱导 E-钙粘蛋白的表达和平分 GlcNAc 分支的 N-糖基化，从而阻断上皮间质转化和淋巴转移
DOI：
10.1038/s41416-020-1007-3
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发表时间：
2020-10
影响因子：
8.8
通讯作者：
Guo C
中科院分区：
文献类型：
--
作者：
Wang Y;Li Q;Niu L;Xu L;Guo Y;Wang L;Guo C
【摘要】：背景作为戊糖磷酸途径的限速酶,葡萄糖-6-磷酸脱氢酶(G6PD)在肿瘤进展中发挥着重要作用,但G6PD控制癌症转移的确切机制仍不清楚。方法采用免疫组织化学方法分析口腔鳞状细胞癌(OSCC)切除标本中G6PD的表达。通过 Transwell 实验、伤口愈合实验、蛋白质印迹和凝集素印迹、质谱分析、ChIP-PCR 和荧光素酶报告基因实验测定 G6PD 抑制对 OSCC 细胞系的影响和机制。采用BALB/c-裸鼠建立原位异种移植模型。结果105例OSCC患者肿瘤中G6PD表达与淋巴转移及预后相关。体外细胞研究表明，G6PD 抑制会损害细胞迁移、侵袭和上皮间质转化。此外，G6PD 敲低激活了 JNK 通路，然后阻断 AKT/GSK-3β/Snail 轴以诱导 E-Cadherin 表达，并转录调节 MGAT3 表达以促进 E-Cadherin 的 GlcNAc 分支 N-糖基化。原位异种移植模型进一步证实，脱氢表雄酮降低了OSCC的淋巴转移率，而抑制JNK可部分逆转这种情况。结论G6PD的抑制通过激活JNK通路促进E-Cadherin的表达并平分E-Cadherin的GlcNAc分支的N-糖基化，从而作用于OSCC的转移。
BackgroundAs 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.MethodsG6PD 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.ResultsG6PD 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 regulatedMGAT3expression 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.ConclusionsSuppression 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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