Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.

中文翻译：

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O-GlcNAc 酰化通过 miR-101-O-GlcNAc/EZH2 调节反馈回路促进结直肠癌转移。

晚期结直肠癌（CRC）是最致命的癌症之一，转移患者的5年生存率极低。上皮间质转化（EMT）被认为对于转移性结直肠癌至关重要，但这种效应的基本分子基础仍然未知。在这里，我们发现 O-GlcNAcylation 是一种参与癌症代谢重编程的独特翻译后修饰 (PTM)，可增加 CRC 的转移能力。转移性结直肠癌组织和细胞系中 O-GlcNAc 酰化水平升高，这可能通过增强 EZH2 蛋白稳定性和功能来促进 EMT。O-GlcNAcylation 水平较高的 CRC 患者表现出较大的淋巴结转移潜力和较低的总生存率。生物信息分析和荧光素酶报告基因检测表明，O-GlcNAc 酰化转移酶 (OGT) 和 EZH2 均受到 microRNA-101 的转录后抑制。此外，miR-101启动子区的O-GlcNAcylation和H3K27me3修饰进一步抑制miR-101的转录，导致转移性CRC中OGT和EZH2上调，从而形成恶性循环。在这项研究中，我们证明了受 microRNA-101 负调控的 O-GlcNAcylation 可能通过增强 EZH2 蛋白的稳定性和功能来促进 CRC 转移。减少 O-GlcNAc 酰化可能是转移性结直肠癌的潜在治疗策略。