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Published on: March 27, 2020
RNF207 promotes colorectal cancer growth by regulating the Hippo-YAP pathway via enhanced MST1 ubiquitination and
Meng Wang1, Xing Wen1, Mei Yang2
1Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Chengdu, 610031, China.
Background:
Colorectal cancer ranks second in global mortality rates, yet its molecular pathogenesis remains incompletely understood. Accumulating evidence indicates that E3 ubiquitin ligases modulate the activity and stability of critical oncoproteins via ubiquitination, positioning these enzymes as promising therapeutic targets for cancer intervention. The E3 ligase Ring finger protein 207 (RNF207), characterized as a regulator involved in heart disease, has not been investigated in colorectal cancer.
Methods:
We constructed RNF207 overexpression and knockdown colorectal cancer cell lines, and investigated the effects of RNF207 on the proliferation and migration of colorectal cancer cells through experiments such as CCK8, colony formation, migration, and invasion assays. In colorectal cancer cell lines and human colorectal cancer tissues, the influence of RNF207 on the Hippo-YAP signaling pathway was extensively investigated. The mechanism by which RNF207 regulates P-YAP and MST1 was explored through Co-IP and ubiquitination experiments. Finally, the effect of RNF207 on the growth of colorectal cancer was investigated in nude mice.
Results:
Here, we demonstrate that elevated RNF207 expression in colorectal tumors correlates with poor prognosis. Functional studies revealed that RNF207 enhances colorectal cancer cell proliferation, migration. Mechanistically, we identified that RNF207 promotes colorectal cancer progression through MST1-dependent regulation of Hippo-YAP signaling. Specifically, RNF207 interacts with MST1 and induces its proteasomal degradation via K48-linked ubiquitination dependent on the activity of E3 ligase, thereby attenuating YAP phosphorylation and activating YAP-driven transcription. Furthermore, the protein level of RNF207 was significantly negatively correlated with the protein levels of MST1 and P-YAP in colorectal tumors, and reducing the expression of RNF207 can effectively inhibit the growth of colorectal cancer.
Conclusions:
Collectively, our findings uncover a novel oncogenic function of RNF207 in colorectal cancer, whereby it facilitates MST1 degradation through K48 ubiquitination, leading to YAP hyper-activation. Targeting RNF207-MST1-YAP axis may represent a potential therapeutic for colorectal cancer treatment.
Insights
Ring finger protein 207 (RNF207) promotes colorectal cancer growth by degrading MST1, leading to YAP pathway activation. Inhibiting RNF207 offers a potential therapeutic strategy for colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Colorectal cancer (CRC) is a leading cause of cancer mortality with incompletely understood molecular drivers.
- E3 ubiquitin ligases are emerging therapeutic targets in cancer due to their role in regulating oncoprotein stability.
- Ring finger protein 207 (RNF207), an E3 ligase, has not been previously studied in the context of colorectal cancer.
Purpose of the Study:
- To investigate the role and molecular mechanism of RNF207 in colorectal cancer progression.
- To explore the potential of targeting RNF207 as a therapeutic strategy for colorectal cancer.
Main Methods:
- Constructed RNF207 overexpression and knockdown colorectal cancer cell lines.
- Assessed proliferation, migration, and invasion using CCK8, colony formation, and transwell assays.
- Investigated RNF207's impact on the Hippo-YAP signaling pathway via Co-IP and ubiquitination assays.
- Evaluated RNF207's effect on tumor growth in a nude mouse model.
Main Results:
- Elevated RNF207 expression in colorectal tumors correlates with poor prognosis.
- RNF207 enhances colorectal cancer cell proliferation and migration.
- RNF207 promotes colorectal cancer progression by inducing MST1 degradation via K48 ubiquitination, leading to YAP pathway activation.
- Reduced RNF207 expression inhibited colorectal cancer growth in vivo.
Conclusions:
- RNF207 functions as an oncogene in colorectal cancer by degrading MST1 and activating the YAP pathway.
- The RNF207-MST1-YAP axis represents a novel therapeutic target for colorectal cancer treatment.
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