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 2

RNF112 suppresses FOXM1 transcriptional targets and inhibits the malignancy of gastric cancer cells in vitro.

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RNF112 suppresses FOXM1 transcriptional targets and inhibits the maligna...
(A) The luciferase activity of 6×FKH luciferase reporter after RNF112 overexpression. MGC803 and BGC823 cells in 24-well plates were transfected with 6×FKH luciferase reporter and pRL-TK, together with RNF112 plasmids or EV, respectively. The luciferase activity was measured 24 hours later (n = 3). (B–D) Quantitative reverse transcription–PCR (qRT–PCR) analysis (B and C) and immunoblot analysis (D) of the expression of FOXM1 target genes after transfection with RNF112-HA plasmids and EV for 48 hours in MGC803 and BGC823 cells (n = 3). (E and F) Representative images of colony-formation assays (E) and Transwell invasion assays (F) using stably overexpressing EV or RNF112 MGC803 and BGC823 cells. The relative number of colonies and invasive cells was normalized and plotted (n = 3). Scale bar: 400 μm. (G) The luciferase activity of 6×FKH luciferase reporter in WT and RNF112-depleted MGC803 cells (n = 3). (H and I) qRT–PCR analysis (H) and immunoblot analysis (I) of the expression of FOXM1 target genes in WT and RNF112-depleted MGC803 cells (n = 3). (J and K) Representative images of colony-formation assays (J) and Transwell invasion assays (K) using WT and RNF112-depleted MGC803 cells (n = 3). Scale bar: 400 μm. Data are presented as mean ± SD. Statistical significance was calculated using Student’s t test (A–C, E–H, J, and K). *P < 0.05. Complete unedited blots are in the supplemental material.