2. Academic Validation
  3. AKR1B10 dictates c-Myc stability to suppress colorectal cancer metastasis via PP2A nitration

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

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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