The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours.

中文翻译：

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G6PD的O-GlcNAcylation促进了戊糖磷酸途径和肿瘤的生长。

磷酸戊糖途径（PPP）在大分子生物合成中以及在快速增殖的细胞中维持细胞氧化还原同源性中起着至关重要的作用。PPP的上调已在几种类型的癌症中显示。然而，如何调节PPP以赋予癌细胞选择性生长优势尚不清楚。在这里我们显示，葡萄糖6-磷酸脱氢酶（G6PD），PPP的限速酶，响应缺氧而被O-连接的β-N-乙酰基葡糖胺糖动态修饰。糖基化激活G6PD活性并增加通过PPP的葡萄糖通量，从而提供核苷酸和脂质生物合成的前体，并减少抗氧化剂防御的等效物。阻断G6PD的糖基化可降低癌细胞在体外的增殖，并损害体内的肿瘤生长。重要的，G6PD糖基化在人类肺癌中增加。我们的发现揭示了对O-糖基化如何直接调节PPP从而赋予肿瘤选择性生长优势的机械理解。