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RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer

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.

 

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The information you provided highlights the role of Forkhead box M1 (FOXM1) in both normal physiological development and pathological tumorigenesis. The regulation of FOXM1, particularly its degradation, has not been extensively studied. However, researchers used the ON-TARGETplus siRNA library to screen for E3 ligases that could potentially repress FOXM1. Through this screening, they identified RNF112 as a candidate that directly ubiquitinates FOXM1 in gastric cancer.

The direct ubiquitination of FOXM1 by RNF112 leads to a decrease in the transcriptional network of FOXM1. As a result, the proliferation and invasion of gastric cancer cells are suppressed. Furthermore, the researchers discovered that a small-molecule compound called RCM-1, which is already well-established, enhances the interaction between RNF112 and FOXM1. This enhanced interaction further promotes the ubiquitination of FOXM1. Consequently, RCM-1 exhibits promising anticancer effects both in vitro (in cell cultures) and in vivo (in animal models).

The findings of this study demonstrate that RNF112 acts as a suppressor of gastric cancer progression by ubiquitinating FOXM1. The RNF112/FOXM1 axis not only serves as a prognosis biomarker but also represents a potential therapeutic target in gastric cancer. These results highlight the importance of understanding the regulatory mechanisms of FOXM1 and provide insights into novel strategies for the treatment of gastric cancer.

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S6898 RCM-1 RCM-1 is a nontoxic inhibitor of Forkhead box M1 (FOXM1) that suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice. RCM-1 decreases carcinogenesis and nuclear β-catenin.

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