N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis

Ri-Xin Chen,Xiao-Dan Ma,Feng Wang,Jean-Gabrie Judde,Zhi-Zhong Pan,Xin Chen,Xinyuan Guan,Jie-Wei Chen,Kai Han,Olivier Deas,Rui-Hua Xu,Jia-Xing Zhang,Liang-Ping Xia,Ning-Fang Ma,Dan Xie Dan Xie,Feng-Wei Wang,Jing-Ping Yun

doi:10.1038/s41467-019-12651-2

Abstract

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

Highlights

IntroductionCircular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms
Circular RNAs have been implicated in cancer progression through largely unknown mechanisms
In this study, we first demonstrated that circNSUN2, which maps to the 5p15 amplicon in CRCs, is an important circRNA that promotes liver metastasis (LM) in CRC

Summary

Introduction

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. The upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease. CircRNAs can function as miRNA sponges, modulating the activity of miRNAs on related target genes[14,15] or regulate gene expression at both the transcription and splicing levels[18,19]; or can be translated, function as encoded protein[20,21] These findings, taken together, suggest that circRNAs play functional roles in fundamental processes and serve as potential clinical molecular markers, thereby providing new insights into the treatment of human diseases, such as cancer. Our findings suggest that circNSUN2 functions as a critical predictor for LM of CRC patients and/or a potential therapeutic target against CRC

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Conclusion