Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Medical Research Institute, Southwest University, Chongqing, China.
JCI Insight. 2023 Jun 8;8(11):e166698. doi: 10.1172/jci.insight.166698.
Forkhead box M1 (FOXM1) plays a critical role in development physiologically and tumorigenesis pathologically. However, insufficient efforts have been dedicated to exploring the regulation, in particular the degradation of FOXM1. Here, the ON-TARGETplus siRNA library targeting E3 ligases was used to screen potential candidates to repress FOXM1. Of note, mechanism study revealed that RNF112 directly ubiquitinates FOXM1 in gastric cancer, resulting in a decreased FOXM1 transcriptional network and suppressing the proliferation and invasion of gastric cancer. Interestingly, the well-established small-molecule compound RCM-1 significantly enhanced the interaction between RNF112 and FOXM1, which further promoted FOXM1 ubiquitination and subsequently exerted promising anticancer effects in vitro and in vivo. Altogether, we demonstrate that RNF112 suppresses gastric cancer progression by ubiquitinating FOXM1 and highlight the RNF112/FOXM1 axis serves as both prognosis biomarker and therapeutic target in gastric cancer.
叉头框 M1（FOXM1）在生理发育和病理肿瘤发生中起着关键作用。然而，人们在探索其调控机制，特别是 FOXM1 的降解方面，投入的努力还不够。在这里，我们使用了靶向 E3 连接酶的 ON-TARGETplus siRNA 文库来筛选潜在的候选物，以抑制 FOXM1。值得注意的是，机制研究表明，RNF112 在胃癌中直接泛素化 FOXM1，导致 FOXM1 转录网络减少，并抑制胃癌的增殖和侵袭。有趣的是，经过充分验证的小分子化合物 RCM-1 显著增强了 RNF112 和 FOXM1 之间的相互作用，进一步促进了 FOXM1 的泛素化，从而在体外和体内发挥了有前景的抗癌作用。总之，我们证明 RNF112 通过泛素化 FOXM1 抑制胃癌的进展，并强调 RNF112/FOXM1 轴不仅可以作为胃癌的预后生物标志物，还可以作为治疗靶点。
