NDRG2 orchestrates circadian clock stability to suppress tumorigenesis and potentiate oxaliplatin response in colorectal cancer.

Circadian disruption is linked to colorectal cancer (CRC) progression. We investigated the role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) in this context. Intestinal-specific Ndrg2 knockout exacerbated colorectal tumorigenesis in mice under circadian disruption. We identified NDRG2 as a novel stabilizer of the core clock protein Circadian Locomotor Output Cycles Kaput (CLOCK). Mechanistically, NDRG2 bidirectionally regulates CLOCK ubiquitination, inhibiting its degradation by the E3 ligase STIP1 Homology and U-Box Containing Protein 1 (STUB1) while promoting stabilization by the deubiquitinase Ubiquitin Specific Peptidase 8 (USP8). This NDRG2-CLOCK axis was crucial for oxaliplatin sensitivity. Integrated RNA sequencing and functional studies revealed that CLOCK transcriptionally represses Fibroblast Growth Factor 2 (FGF2), a chemoresistance driver. Thus, NDRG2 enhances CLOCK activity to suppress FGF2 and promote oxaliplatin efficacy. Clinically, oxaliplatin-sensitive CRC tissues showed higher NDRG2/CLOCK co-expression and lower FGF2 levels. Our work defines a pathway wherein NDRG2 inhibits tumorigenesis and chemoresistance by stabilizing CLOCK to transcriptionally represses FGF2, linking circadian regulation to therapy response, and nominating the NDRG2-STUB1/USP8-CLOCK-FGF2 axis as a therapeutic target.