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

Author

Listed:
  • 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
    Sun Yat-Sen University)

  • 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
    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
    the University of Hong Kong)

  • Jing-Ping Yun

    (Sun Yat-Sen University Cancer Center
    Sun Yat-Sen University)

  • 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
    Sun Yat-Sen University Cancer Center)

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.

Suggested Citation

  • 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, 2019. "N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12651-2
    DOI: 10.1038/s41467-019-12651-2
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    Cited by:

    1. Qilin Huang & Ziqiang Chu & Zihao Wang & Qiankun Li & Sheng Meng & Yao Lu & Kui Ma & Shengnan Cui & Wenzhi Hu & Wenhua Zhang & Qian Wei & Yanlin Qu & Haihong Li & Xiaobing Fu & Cuiping Zhang, 2024. "circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Dario Dattilo & Gaia Di Timoteo & Adriano Setti & Andrea Giuliani & Giovanna Peruzzi & Manuel Beltran Nebot & Alvaro Centrón-Broco & Davide Mariani & Chiara Mozzetta & Irene Bozzoni, 2023. "The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Wenjuan Zhang & Bowei Zhou & Xiao Yang & Jin Zhao & Jingjuan Hu & Yuqi Ding & Shuteng Zhan & Yifeng Yang & Jun Chen & Fu Zhang & Bingcheng Zhao & Fan Deng & Zebin Lin & Qishun Sun & Fangling Zhang & Z, 2023. "Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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