AKR1B10 dictates c-Myc stability to suppress colorectal cancer metastasis via PP2A nitration

  • Sci Adv. 2025 Aug 22;11(34):eadv6937. doi: 10.1126/sciadv.adv6937.
Xiaoxue Wu  1  2 ,  Shaoqing Huang  1  3 ,  Jialing Gao  1  2 ,  Shuting Huang  2  4 ,  Lulu Chen  1  2 ,  Ziyi Zhao  1  3 ,  Ruihan Pu  2  4 ,  Xiaojing Ma  5 ,  Xianzhi Liu  6 ,  Weiling He  1  6 ,  Mei Song  1  2
Affiliations
  • 1. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510275, China.
  • 2. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510275, China.
  • 3. Center of Hepato-Pancreatico-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 4. School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 5. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 6. Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361000, China.
PMID: 40845116 DOI: 10.1126/sciadv.adv6937
Abstract

Metabolic Enzymes, critical for cellular homeostasis, are frequently co-opted in a disease-specific manner to drive Cancer progression. Here, we identify aldo-keto reductase family 1 member B10 (AKR1B10), down-regulated in gastrointestinal cancers, as a pivotal metastasis suppressor correlating with improved Colorectal Cancer (CRC) prognosis. Mechanistically, AKR1B10 activates protein Phosphatase 2A (PP2A) by preventing redox-regulated nitration of its B56α subunit, preserving holoenzyme assembly and enabling c-Myc dephosphorylation at serine-62. Loss of AKR1B10 disrupts this pathway, stabilizing c-Myc, which drives Integrin signaling and metastatic dissemination in CRC. We further demonstrate that lysine-125 of AKR1B10 is essential for its interaction with PP2A-Cα and B56α nitration, thereby attenuating CRC metastatic aggressiveness. Pharmacological restoration of PP2A activity effectively mitigates metastasis associated with AKR1B10 loss. In addition, c-Myc transcriptionally represses AKR1B10, establishing a feedback loop that sustains its down-regulation and enhances metastatic progression. This study uncovers an antimetastatic mechanism involving AKR1B10-mediated PP2A activation and highlights its potential as a biomarker and therapeutic target.

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