RCC2 and CD24 cooperate to modulate prostate cancer progression through vimentin ubiquitination and β-catenin activation.

Abstract

CD24 promotes prostate cancer progression and metastasis by disrupting the ARF-NPM interaction and impairing p53 signaling. However, the mechanisms underlying CD24-driven metastasis remain unclear. This study identifies a novel interaction between CD24 and Regulator of Chromosome Condensation 2 (RCC2), a protein involved in cell proliferation and migration. IHC analysis of prostate adenocarcinoma samples showed frequent coexpression of CD24 (49%) and RCC2 (82%) with a positive correlation between coexpression of CD24 (49%) and RCC2 (82%). Functional assays revealed complex roles: RCC2 KO suppressed proliferation but increased migration and invasion, while CD24 KO reduced both proliferation and migration. Dual KO of CD24 and RCC2 further inhibited proliferation but had varied effects on migration. In mouse xenografts, RCC2 KO increased lung metastasis without significantly affecting primary tumor growth, while CD24 KO reduced both tumor growth and metastasis. Mechanistically, RCC2 controls migration by promoting ubiquitination and degradation of vimentin, affecting cytoskeletal dynamics. In contrast, CD24 targets RCC2 for degradation, thereby regulating β-catenin signaling. Notably, RCC2 KO enhances β-catenin activity by suppressing inhibitors AXIN2 and APC, whereas CD24 KO inhibits this pathway. These findings reveal a regulatory loop where CD24 and RCC2 reciprocally control proliferation and metastasis, positioning the CD24-RCC2 axis as a promising therapeutic target in prostate cancer.