PRDX1 drives colorectal cancer progression and immune microenvironment remodeling by facilitating PRMT5 nuclear translocation to activate Wnt/β-catenin signaling.

Abstract

Hyperactivation of Wnt/β-catenin signaling drives colorectal cancer (CRC) progression and contributes to an immunosuppressive tumor microenvironment. Although peroxiredoxin-1 (PRDX1) is overexpressed in CRC and correlated with poor prognosis, its mechanistic role in Wnt/β-catenin-mediated immune evasion remains unclear. Through transcriptomic sequencing and co-immunoprecipitation, we identified PRDX1-interacting proteins and validated their functional roles via luciferase assays, mutagenesis, and pharmacological approaches in syngeneic models. Results demonstrated that PRDX1 knockout attenuated Wnt/β-catenin signaling in AOM/DSS-induced CRC mice. In cellular models, PRDX1 knockdown inhibited nuclear translocation of β-catenin by promoting its ubiquitination. Mechanistically, PRDX1 functions as a redox-sensitive chaperone that interacts with protein arginine methyltransferase 5 (PRMT5) in the cytoplasm and facilitates its nuclear translocation. This was associated with increased H3R2me2 and H3R8me2 levels, upregulation of DVL3 transcription, and subsequent Wnt/β-catenin activation. The interaction was abrogated by disrupting the Rossmann-fold or β-barrel domains of PRMT5, or by introducing the R368A catalytic mutation, suggesting that these domains are important for the PRDX1-PRMT5 association. Importantly, pharmacologically inhibiting PRMT5 suppressed PRDX1-driven tumor growth and alleviated immunosuppression in vivo by dampening Wnt/β-catenin signaling. These findings identify a novel PRDX1-PRMT5 axis that activates Wnt/β-catenin signaling, highlighting a potential therapeutic strategy for CRC by targeting this pathway to suppress tumor progression and remodel the immune microenvironment.