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.

Neddylation 是一种翻译后蛋白质修饰，已观察到它在各种癌症中被过度激活。UBC12 是 neddylation 途径中的两个关键 E2 酶之一。报告表明，UBC12 缺乏可能会抑制肺癌细胞，因此 UBC12 可能在肿瘤进展中发挥重要作用。然而，缺乏关于 UBC12 在癌症中的表达谱及其与癌症预后的关系的系统研究。在这项研究中，我们全面分析了 UBC12 在不同癌症类型中的表达，发现 UBC12 在大多数癌症中显着过表达 (17/21)，这种症状与包括胃癌在内的癌症患者的生存率呈负相关。这些结果表明 UBC12 适合作为癌症治疗的潜在靶标。现在，尚未发现针对 UBC12 的有效抑制剂。我们筛选了一个天然产物库，首次发现牛蒡甙元可显着抑制 UBC12 酶活性和 cullin neddylation。新发现抑制 UBC12 酶活性有助于牛蒡苷元抑制癌细胞恶性表型的作用。此外，我们进行了蛋白质组学分析，发现牛蒡甙元干预了 cullin 下游信号通路和底物，例如肿瘤抑制因子 PDCD4。总之，这些结果证明了 UBC12 作为癌症治疗的潜在治疗靶点的重要性，并且首次证明了牛蒡甙元作为靶向 UBC12 酶活性的潜在化合物的适用性。因此，