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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月31日

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  • Xiang Zhang,
  • Yuqin Di,
  • Youpeng Wang,
  • Jiale Qin,
  • Lvlan Ye,
  • Xiangqiong Wen,
  • Zunfu Ke,
  • Ziyang Wang,
  • Weiling He

摘要

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.