NUF2 activated by YY1 promotes prostate cancer malignancy via p38/MAPK signaling axis and serves as a therapeutic target

Abstract

Prostate cancer (PCa) is one of the most prevalent malignancies in the male urogenital system. Despite extensive research into its mechanisms of initiation and progression, the full scope of its pathophysiology remains insufficiently understood. This study demonstrated that NUF2 was significantly overexpressed in PCa, with its elevated levels correlating with poor patient survival outcomes. Silencing NUF2 notably impaired PCa cell proliferation and metastasis in both in vitro and in vivo models, whereas its overexpression promoted these processes. Additionally, YY1 was identified as a direct transcriptional activator of NUF2, binding to its promoter and enhancing its oncogenic effects through activation of downstream targets. Moreover, NUF2 promoted PCa progression by recruiting p38, accelerating its phosphorylation, and activating the p38/MAPK signaling pathway. Through the PubChem database, fisetin was identified as a small molecule inhibitor of NUF2. Fisetin effectively inhibited PCa cell proliferation, and NUF2 overexpression reversed this inhibitory effect. In conclusion, our results suggest that NUF2 overexpression accelerated PCa progression via the p38/MAPK pathway, regulated by YY1. The identification of fisetin as a NUF2 inhibitor offers a promising therapeutic strategy for targeting NUF2 to impede PCa growth. NUF2 may thus serve as a valuable prognostic biomarker and a potential therapeutic target for PCa.