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<p>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 <i>Ndrg2</i> 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 <i>Fibroblast Growth Factor 2</i> (<i>FGF2</i>), 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 <i>FGF2</i>, linking circadian regulation to therapy response, and nominating the NDRG2-STUB1/USP8-CLOCK-FGF2 axis as a therapeutic target.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年5月19日

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  • Ruikai Li,
  • Ruxin Ding,
  • Hanjun Dan,
  • Kunli Du,
  • Gaozan Zheng,
  • Siyuan Wang,
  • Lili Duan,
  • Pengfei Wang,
  • Liangliang Shen,
  • Lin Feng,
  • Pan Zhao,
  • Jiajia Wang,
  • Dan Feng,
  • Fengsu Wu,
  • Yumao Yang,
  • Ziting Zhou,
  • Liaoran Niu,
  • Weidong Wang,
  • Xinyu Qiao,
  • Jianting Yang,
  • Fan Feng,
  • Jianyong Zheng,
  • Jian Zhang

摘要

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.