Arctigenin impairs UBC12 enzyme activity and cullin neddylation to attenuate cancer cells

Yi-fan Chen1, Run-zhi Liu1, Wen-wen Ying1, Yue-ning Yang1, Sen-feng Xiang1, Xue-jing Shao1, Ji Cao1,2,3, Yan-qi Zhang4, Bo Yang1, Qiao-jun He1,2,3, Mei-dan Ying1,2,5
1 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 Cancer Center, Zhejiang University, Hangzhou 310058, China
3 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China
4 Department of Pharmacy, The Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou 310007, China
5 Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
Correspondence to: Bo Yang:, Qiao-jun He:, Mei-dan Ying:,
DOI: 10.1038/s41401-022-00992-6
Received: 11 May 2022
Accepted: 28 August 2022
Advance online: 22 September 2022


Neddylation is a type of posttranslational protein modification that has been observed to be overactivated in various cancers. UBC12 is one of two key E2 enzymes in the neddylation pathway. Reports indicate that UBC12 deficiency may suppress lung cancer cells, such that UBC12 could play an important role in tumor progression. However, systematic studies regarding the expression profile of UBC12 in cancers and its relationship to cancer prognosis are lacking. In this study, we comprehensively analyzed UBC12 expression in diverse cancer types and found that UBC12 is markedly overexpressed in most cancers (17/21), a symptom that negatively correlates with the survival rates of cancer patients, including gastric cancer. These results demonstrate the suitability of UBC12 as a potential target for cancer treatment. Currently, no effective inhibitor targeting UBC12 has been discovered. We screened a natural product library and found, for the first time, that arctigenin has been shown to significantly inhibit UBC12 enzyme activity and cullin neddylation. The inhibition of UBC12 enzyme activity was newly found to contribute to the effects of arctigenin on suppressing the malignant phenotypes of cancer cells. Furthermore, we performed proteomics analysis and found that arctigenin intervened with cullin downstream signaling pathways and substrates, such as the tumor suppressor PDCD4. In summary, these results demonstrate the importance of UBC12 as a potential therapeutic target for cancer treatment, and, for the first time, the suitability of arctigenin as a potential compound targeting UBC12 enzyme activity. Thus, these findings provide a new strategy for inhibiting neddylation-overactivated cancers.
Keywords: UBC12; arctigenin; neddylation; cancer therapy; PDCD4

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