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

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.

SUBMITTER: Xiang Zhang

PROVIDER: S-SCDT-10_1038-S44318-025-00416-1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundHypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1alpha, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis.Methodology/principal findingsBy using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1alpha protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1alpha protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1alpha protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2-induced HIF-1alpha stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1alpha degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1alpha protein. We also showed that bcl-2, HIF-1alpha and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1alpha protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1alpha protein during hypoxia, and in particular the isoform HSP90beta is the main player in this phenomenon.Conclusions/significanceWe identified the stabilization of HIF-1alpha protein as a mechanism through which bcl-2 induces the activation of HIF-1 in hypoxic tumour cells involving the beta isoform of molecular chaperone HSP90.

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

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