Department of Gastroenterology, Beijing Friendship Hospital, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Capital Medical University, Beijing 100050, P.R. China.
Exp Biol Med (Maywood). 2022 Sep;247(17):1518-1528. doi: 10.1177/15353702221101810. Epub 2022 Jun 20.
The hexosamine biosynthetic pathway (HBP) is connected to abnormal N- and O-linked protein glycosylation in cancer, which performs critical roles in tumorigenesis. However, the regulation mechanisms of HBP and its role in colorectal cancer (CRC) progression remain unexplained. This study analyzed the expression level of phosphoglucomutase 3 (PGM3), a key enzyme in HBP, and identified its function in CRC cell lines. Analysis of publicly available CRC microarray data determined that PGM3 is upregulated in CRC tumor tissues. Furthermore, functional experiments emphasized the significant roles of PGM3 in facilitating CRC cell proliferation and migration. Mechanistically, we demonstrated that the activity of β-catenin in CRC was maintained by PGM3-mediated O-GlcNAcylation. PGM3 knockdown or inhibition of O-GlcNAc transferase decreased β-catenin activity and the expression levels of its downstream targets. Collectively, our findings indicate that PGM3 exhibits tumor-promoting roles by elevating O-GlcNAcylation level and maintaining β-catenin activity, and might serve as a prognostic biomarker and treatment target in CRC.
己糖胺生物合成途径（HBP）与癌症中异常的 N-和 O-连接蛋白糖基化有关，其在肿瘤发生中发挥着关键作用。然而，HBP 的调控机制及其在结直肠癌（CRC）进展中的作用仍未得到解释。本研究分析了 HBP 关键酶磷酸葡萄糖变位酶 3（PGM3）的表达水平，并鉴定了其在 CRC 细胞系中的功能。对公开可用的 CRC 微阵列数据的分析表明，PGM3 在 CRC 肿瘤组织中上调。此外，功能实验强调了 PGM3 促进 CRC 细胞增殖和迁移的重要作用。在机制上，我们证明了 PGM3 通过介导 O-GlcNAc 化来维持 CRC 中 β-连环蛋白的活性。PGM3 敲低或 O-GlcNAc 转移酶抑制剂降低了 β-连环蛋白的活性及其下游靶标的表达水平。总之，我们的研究结果表明，PGM3 通过提高 O-GlcNAc 化水平和维持 β-连环蛋白的活性来发挥促肿瘤作用，可能作为 CRC 的预后标志物和治疗靶点。
