NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation

Yuanbo Hu,Sian Chen,Xiangwei Sun,Xiangyang Xue,Chenbin Chen,Zhiyuan Chen,Mingdong Lu,Xianjing Hu,Xinyu Shi,Bujian Pan,Xian Shen,Yingying Hu,Xinya Tong

doi:10.1038/s41419-021-04127-3

Abstract

The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.

Highlights

Human gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related mortality [1]
NSUN2 was highly expressed in GC and associated with a poor prognosis According to The Cancer Genome Atlas (TCGA) data, we found that NSUN2 was overexpressed in various cancers (Fig. 1C); we speculated that NSUN2 might act as a common oncogene that participates in human cancer
The results showed that NSUN2 was closely connected with other m5C regulators and the global expression level of m5C regulators was significantly correlated with the overall survival of patients

Summary

INTRODUCTION

Human gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related mortality [1]. RNA modifications, such as N6-methyladenosine (m6A), play a nonnegligible role in epigenetic gene regulation and cellular functions [4, 5], which are closely associated with numerous human diseases, including cancer [6], neurological disorders [7], and immune dysregulation [8]. The Aly/REF export factor (ALYREF) and Y-box binding protein 1 (YBX1), characterized as readers, recognize and bind the m5C motif, and exert further biological functions [13, 14]. These regulators, in coordination with m5C modifications, are known to participate in the progression of multiple tumors.

MATERIALS AND METHODS

RESULTS

DISCUSSION