Fbxo2 suppresses prostate cancer progression by regulating YTHDF2 ubiquitination and degradation

TL;DR

Fbxo2 helps prevent prostate cancer by breaking down a harmful protein called YTHDF2, which could lead to new treatments.

Contribution

This study identifies Fbxo2 as a novel E3 ubiquitin ligase that suppresses prostate cancer by targeting YTHDF2 for degradation.

Findings

Fbxo2 is downregulated in prostate cancer and its higher expression correlates with better patient prognosis.

Fbxo2 reduces prostate cancer cell proliferation and metastasis by ubiquitinating and degrading YTHDF2.

YTHDF2 promotes prostate cancer progression by modulating m6A methylation of CDKN1C mRNA.

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.

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