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

Ri-Xin Chen, Xin Chen, Liang-Ping Xia, Jia-Xing Zhang, Zhi-Zhong Pan, Xiao-Dan Ma, Kai Han, Jie-Wei Chen, Jean-Gabrie Judde, Olivier Deas, Feng Wang, Ning-Fang Ma, Xinyuan Guan, Jing-Ping Yun, Feng-Wei Wang (), Rui-Hua Xu () and Xie ()
Additional contact information
Ri-Xin Chen: Sun Yat-Sen University Cancer Center
Xin Chen: Sun Yat-Sen University Cancer Center
Liang-Ping Xia: Sun Yat-Sen University Cancer Center
Jia-Xing Zhang: Sun Yat-Sen University Cancer Center
Zhi-Zhong Pan: Sun Yat-Sen University Cancer Center
Xiao-Dan Ma: Sun Yat-Sen University Cancer Center
Kai Han: Sun Yat-Sen University Cancer Center
Jie-Wei Chen: Sun Yat-Sen University Cancer Center
Jean-Gabrie Judde: XenTech SAS
Olivier Deas: XenTech SAS
Feng Wang: Sun Yat-Sen University Cancer Center
Ning-Fang Ma: Affiliated Cancer Hospital & Institute of Guangzhou Medical University
Xinyuan Guan: Sun Yat-Sen University Cancer Center
Jing-Ping Yun: Sun Yat-Sen University Cancer Center
Feng-Wei Wang: Sun Yat-Sen University Cancer Center
Rui-Hua Xu: Sun Yat-Sen University Cancer Center
Xie: Sun Yat-Sen University Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12651-2

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