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Updated: Jan 7, 2026
Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
Fbxo2 suppresses prostate cancer progression by regulating YTHDF2 ubiquitination and degradation
Xinyu Xu1,2, Guangcheng Dai1, Chun-Ling Liu3
1Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Abstract:
Deregulation of E3 ubiquitin ligases is associated with increased proliferation and metastasis in prostate cancer (PCa); however, the underlying mechanisms remain largely unclear. This study aimed to explore the role of Fbxo2, a SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase, in PCa progression. Analysis of prostate tissue samples revealed that Fbxo2 is downregulated in PCa, and higher Fbxo2 expression correlates with better patient prognosis. Functional assays conducted both in vitro and in vivo demonstrated that Fbxo2 reduces cell proliferation and metastasis in PCa. Using co-immunoprecipitation mass spectrometry (co-IP-MS), co-IP, western blotting, and ubiquitin assays, we identified that m6A reader YTHDF2, an oncoprotein that is upregulated in PCa, was a substrate of Fbxo2-mediated degradation. Notably, Fbxo2 mutants lacking the C-terminal region were less effective in promoting YTHDF2 ubiquitination and destruction. Furthermore, lysine 286 (K286) of YTHDF2 was identified as the key ubiquitination site. A series of rescue experiments revealed that silencing or overexpressing YTHDF2 modulated the effects of Fbxo2 knockdown or overexpression, confirming their functional interplay. Mechanistically, YTHDF2 enhanced the PCa progression and metastasis by modulating the m6A methylation of CDKN1C mRNA. Together, these findings suggest that Fbxo2 axis may serve as a potential prognostic marker and therapeutic target in PCa.
Insights
F-box protein 2 (Fbxo2) acts as a tumor suppressor in prostate cancer (PCa) by targeting the oncoprotein YTHDF2 for degradation. Restoring Fbxo2 levels may offer a new therapeutic strategy for PCa patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- E3 ubiquitin ligase deregulation is linked to prostate cancer (PCa) progression, but mechanisms are unclear.
- F-box protein 2 (Fbxo2), an SCF E3 ubiquitin ligase component, has an unknown role in PCa.
- YTHDF2 is an oncoprotein upregulated in PCa, promoting tumor progression.
Purpose of the Study:
- To investigate the role of Fbxo2 in prostate cancer progression.
- To identify Fbxo2 targets and elucidate its mechanism of action in PCa.
Main Methods:
- Analysis of prostate tissue samples for Fbxo2 expression.
- In vitro and in vivo functional assays to assess Fbxo2's effect on PCa cells.
- Co-immunoprecipitation mass spectrometry (co-IP-MS) and western blotting to identify Fbxo2 targets.
- Ubiquitin assays and site-directed mutagenesis to confirm YTHDF2 ubiquitination.
- Rescue experiments to validate functional interplay between Fbxo2 and YTHDF2.
Main Results:
- Fbxo2 is downregulated in PCa, and its higher expression correlates with better prognosis.
- Fbxo2 overexpression inhibits PCa cell proliferation and metastasis.
- YTHDF2 is identified as a substrate of Fbxo2-mediated ubiquitination and degradation.
- Lysine 286 (K286) of YTHDF2 is the key ubiquitination site.
- YTHDF2 promotes PCa progression by modulating CDKN1C mRNA's m6A methylation.
Conclusions:
- Fbxo2 functions as a tumor suppressor in prostate cancer.
- The Fbxo2-YTHDF2 axis regulates PCa cell proliferation and metastasis.
- Fbxo2 may serve as a prognostic biomarker and therapeutic target for PCa.
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