2. Academic Validation
  3. SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis

SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis

  • EMBO J. 2025 May;44(9):2514-2540. doi: 10.1038/s44318-025-00416-1.
Xiang Zhang # 1,  Yuqin Di # 1 2,  Youpeng Wang # 3,  Jiale Qin 1,  Lvlan Ye 4,  Xiangqiong Wen 5,  Zunfu Ke 6 7,  Ziyang Wang 8,  Weiling He 9
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 2 Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 3 Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
  • 4 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 Department of General Surgery, The First Affiliated Hospital of Nanchang University, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 6 Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. kezunfu@mail.sysu.edu.cn.
  • 7 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. kezunfu@mail.sysu.edu.cn.
  • 8 Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. wangzy256@mail.sysu.edu.cn.
  • 9 Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China. wlhe@xah.xmu.edu.cn.
  • # Contributed equally.
PMID: 40164945 DOI: 10.1038/s44318-025-00416-1
Abstract

Metastasis is the primary cause of death in patients with colorectal Cancer (CRC). Hypoxia is a hallmark of solid tumors that promotes cellular metabolic adaptation and dissemination. However, the mechanisms linking hypoxia-regulated metabolic adaptation to CRC metastasis remain unclear. Here, we found that inorganic pyrophosphatase 2 (PPA2) suppresses metastatic progression of CRC via its Phosphatase function. PPA2 expression levels are reduced in CRC specimen and correlate with enhanced response to hypoxia by promoting hypoxia-inducible factor-1 (HIF-1) signaling to promote CRC cell glycolysis and dissemination. Mechanistically, PPA2 decreases HIF-1alpha stability through non-canonical ubiquitin-mediated proteasomal degradation via recruitment of E3 Ligase NEDD4. Furthermore, PPA2 directly dephosphorylates NEDD4 at threonine 758 residue, resulting in its activation. Under hypoxic stress, NAD-dependent protein deacetylase sirtuin-5 promotes the dissociation of PPA2 and NEDD4 by inducing PPA2 desuccinylation at lysine 176, contributing to the improved stability of HIF-1alpha under hypoxic conditions. Our findings reveal a tumor-suppressive role of PPA2 in HIF-1alpha-dependent colorectal Cancer, providing a potential therapeutic target and prognostic strategy.

Keywords

HIF-1α; Hypoxia; Metastatic Colorectal Cancer; NEDD4; PPA2 Succinylation.

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