RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer
Shengwei Zhang, Jing Wang, Weichao Hu, Lijiao He, Qingyun Tang, Jie Li, Mengmeng Jie, Xinzhe Li, Cheng Liu, Qin Ouyang, Shiming Yang, Changjiang Hu
Shengwei Zhang, Jing Wang, Weichao Hu, Lijiao He, Qingyun Tang, Jie Li, Mengmeng Jie, Xinzhe Li, Cheng Liu, Qin Ouyang, Shiming Yang, Changjiang Hu
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Research Article Gastroenterology Oncology

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

Abstract

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.

Authors

Shengwei Zhang, Jing Wang, Weichao Hu, Lijiao He, Qingyun Tang, Jie Li, Mengmeng Jie, Xinzhe Li, Cheng Liu, Qin Ouyang, Shiming Yang, Changjiang Hu

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Figure 3

RNF112 suppresses gastric cancer malignant behaviors in vivo.

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RNF112 suppresses gastric cancer malignant behaviors in vivo. (A) Tumors...
(A) Tumors were harvested after s.c. injection of MGC803 cells with stable overexpression of RNF112 in nude mice. On day 19, tumors were removed from the sacrificed mice and used for subsequent analysis (n = 5). (B) Tumor growth curves of xenograft of the EV and RNF112 overexpression groups (n = 5). (C) Tumor weight was measured after the mice were sacrificed (n = 5). (D) Immunoblot analysis of FOXM1 and RNF112 expression of the tumors. (E) Quantitative reverse transcription–PCR analysis of FOXM1 downstream genes in the above tumors (n = 5). (F) IHC staining of PCNA, Ki67, FOXM1, and RNF112 in the indicated groups. (G) Bioluminescence imaging of representative mice and statistical analysis of the luminescence intensity (n = 5). (H) H&E staining of the representative metastatic lesions in the lung of nude mice and the statistical analysis of the relative tumor area (n = 5). Scale bar: 50 μm. Data are presented as mean ± SD. Statistical significance was calculated using Student’s t test (C, E, G, and H). *P < 0.05. Complete unedited blots are in the supplemental material.