O- GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer

• 成果类型: Article
• 署名作者: Zhu, Qiang; Li, Jingchao; Sun, Haofan; Fan, Zhiya; Hu, Jiating; Chai, Siyuan; Lin, Bingyi; Wu, Liming; Qin, Weijie; Wang, Yong; Hsieh-Wilson, Linda C.; Yi, Wen
• 署名单位: Zhejiang University; Zhejiang University; Zhejiang University; California Institute of Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14623
• DOI: 10.1073/pnas.2408354121
• 发表日期: 2024-10-29
• 关键词: n-acetylglucosamine; glcnac; protein; metabolism

摘要

Aerobic glycolysis and immune evasion are two key hallmarks of cancer. However, how these two features are mechanistically linked to promote tumor growth is not well understood. Here, we show that the glycolytic enzyme enolase-1 (ENO1) is dynamically modified with an O- linked beta-N- acetylglucosamine (O- GlcNAcylation), and simultaneously regulates aerobic glycolysis and immune evasion via differential glycosylation. Glycosylation of threonine 19 (T19) on ENO1 promotes its glycolytic activity via the formation of active dimers. On the other hand, glycosylation of serine 249 (S249) on ENO1 inhibits its interaction with PD- L1, decreases association of PD- L1 with the E3 ligase STUB1, resulting in stabilization of PD- L1. Consequently, blockade of T19 glycosylation on ENO1 inhibits glycolysis, and decreases cell proliferation and tumor growth. Blockade of S249 glycosylation on ENO1 reduces PD- L1 expression and enhances T cell-mediated immunity against tumor cells. Notably, elimination of glycosylation at both sites synergizes with PD- L1 monoclonal antibody therapy to promote antitumor immune response. Clinically, ENO1 glycosylation levels are up- regulated and show a positive correlation with PD- L1 levels in human colorectal cancers. Thus, our findings provide a mechanistic understanding of how O- GlcNAcylation bridges aerobic glycolysis and immune evasion to promote tumor growth, suggesting effective therapeutic opportunities.