DSN1 promotes colorectal cancer metastasis by Inhibiting FZR1-Mediated ubiquitination of c-MYC

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need to clarify its molecular drivers. Here, we identify DSN1 as a key promoter of CRC invasion and metastasis. Analysis of clinical samples and public datasets revealed that DSN1 is significantly upregulated in CRC tissues and associated with poor overall survival. Functional assays demonstrated that DSN1 knockdown markedly suppressed CRC cell migration and invasion in vitro and reduced metastases in vivo. Mechanistically, DSN1 knockdown accelerated c-MYC protein degradation without affecting its mRNA levels. Cycloheximide chase and proteasome inhibition assays confirmed that DSN1 stabilizes c-MYC by preventing its ubiquitin-proteasome-mediated degradation. We further identified FZR1 as a c-MYC targeting E3 ligase and showed that DSN1 competes with c-MYC for FZR1 binding, thereby attenuating c-MYC ubiquitination. Rescue experiments confirmed that c-MYC overexpression reversed the anti-metastatic effects of DSN1 silencing. Collectively, our findings uncover a DSN1-FZR1-c-MYC regulatory axis that sustains c-MYC stability and drives CRC progression, highlighting DSN1 as a potential therapeutic target.