Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer

Meng Wang, Yue Li, Yunyun Xiao, Muwen Yang, Jinxin Chen, Yunting Jian, Xin Chen, Dongni Shi, Xiangfu Chen, Ying Ouyang, Lingzhi Kong, Xinjian Huang, Jiewen Bai, Chuyong Lin () and Libing Song ()
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Meng Wang: Sun Yat-sen University Cancer Center
Yue Li: Sun Yat-sen University Cancer Center
Yunyun Xiao: Sun Yat-sen University Cancer Center
Muwen Yang: Sun Yat-sen University Cancer Center
Jinxin Chen: Sun Yat-sen University Cancer Center
Yunting Jian: Sun Yat-sen University Cancer Center
Xin Chen: Guangzhou Medical University
Dongni Shi: Sun Yat-sen University Cancer Center
Xiangfu Chen: Sun Yat-sen University Cancer Center
Ying Ouyang: Sun Yat-sen University Cancer Center
Lingzhi Kong: Sun Yat-sen University Cancer Center
Xinjian Huang: Sun Yat-sen University Cancer Center
Jiewen Bai: Sun Yat-sen University Cancer Center
Chuyong Lin: Sun Yat-sen University Cancer Center
Libing Song: Sun Yat-sen University Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer’s poor prognosis; however, nicotine’s role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.

Date: 2021
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DOI: 10.1038/s41467-021-27348-8

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