Zhang Xiang, Di Yuqin, Wang Youpeng, Qin Jiale, Ye Lvlan, Wen Xiangqiong, Ke Zunfu, Wang Ziyang, He Weiling
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
EMBO J. 2025 May;44(9):2514-2540. doi: 10.1038/s44318-025-00416-1. Epub 2025 Mar 31.
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.
转移是结直肠癌（CRC）患者死亡的主要原因。缺氧是实体瘤的一个标志，可促进细胞代谢适应和扩散。然而，将缺氧调节的代谢适应与CRC转移联系起来的机制仍不清楚。在这里，我们发现无机焦磷酸酶2（PPA2）通过其磷酸酶功能抑制CRC的转移进程。CRC标本中PPA2表达水平降低，并且通过促进缺氧诱导因子-1（HIF-1）信号传导以促进CRC细胞糖酵解和扩散，与对缺氧的增强反应相关。机制上，PPA2通过募集E3连接酶NEDD4，通过非经典泛素介导的蛋白酶体降解降低HIF-1α的稳定性。此外，PPA2直接使NEDD4的苏氨酸758残基去磷酸化，导致其激活。在缺氧应激下，NAD依赖性蛋白脱乙酰酶sirtuin-5通过诱导PPA2赖氨酸176位点去琥珀酰化促进PPA2与NEDD4解离，有助于缺氧条件下HIF-1α稳定性的提高。我们的研究结果揭示了PPA2在HIF-1α依赖性结直肠癌中的肿瘤抑制作用，提供了一个潜在的治疗靶点和预后策略。
