O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit

Mingzuo Jiang,Yongzhan Nie,Yi Chu,Yulong Shang,Song Zhang,Kaichun Wu,Xiaoyong Yang,Mengbin Li,Di Chen,Nan Wu,Sijun Hu,Weijie Wang,Jie Liang,Daiming Fan,Bing Xu,Xiaowei Li

doi:10.1038/s41388-018-0435-5

Abstract

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.

Highlights

These authors contributed : Mingzuo Jiang, Bing Xu, Xiaowei Li, Yulong ShangElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Tumor metastasis represents a multistep cellular biological event termed the invasion-metastasis cascade, whereby epithelial cells in primary tumors disseminate as cancer cells to anatomically distant organs and subsequently adapt to the foreign microenvironments [1]
High OGlcNAcylation was not correlated with age, gender, tumor location, or size (P > 0.05, Table 1) but was significantly positively associated with lymph node metastasis and the American Joint Committee on Cancer (AJCC) status (P < 0.01, Table 1)
To investigate the expression of O-GlcNAcylation transferase (OGT) and OGA in human colorectal cancer (CRC) tissues, we reviewed the Cancer Genome Atlas (TCGA) by the Oncomine database and found that the OGT mRNA level was significantly elevated in all types of CRC, including cecum adenocarcinoma, colon adenocarcinoma, colon mucinous adenocarcinoma, rectal adenocarcinoma, and rectal mucinous adenocarcinoma, compared with that in normal colorectal tissues (Fig. 1d)

Summary

Introduction

These authors contributed : Mingzuo Jiang, Bing Xu, Xiaowei Li, Yulong Shang. Tumor metastasis represents a multistep cellular biological event termed the invasion-metastasis cascade, whereby epithelial cells in primary tumors disseminate as cancer cells to anatomically distant organs and subsequently adapt to the foreign microenvironments [1]. Increased risk of cancerrelated death is a serious consequence of metastasis [2]. Despite significant advances in the detection and treatment of colorectal cancer (CRC), many patients still die from local or distant metastasis [2,3,4]. Most of the current investigations are focused on genetic mechanisms and cellular signaling pathways, and little is known about the metabolic and epigenetic mechanisms involved in this process

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Results

Conclusion