SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response

Du, Shi Chun; Zhu, Lan; Wang, Yu Xing; Liu, Jie; Zhang, Die; Chen, Yu Lu; Peng, Qing; Liu, Wei; Liu, Bin

doi:10.1186/s12935-018-0722-9

Cited by 28 publications

(14 citation statements)

References 19 publications

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“…HIF-1 α is an oxygen-dependent subunit of HIF-1 that forms the heterodimer structure of HIF-1 with another constitutively expressed protein, the HIF-1β subunit ( Li et al, 2016 ). The activation of HIF-1α promotes tumor angiogenesis ( Du et al, 2019 ), promotes distant metastasis of tumor cells ( Balamurugan, 2016 ), mediates aerobic glycolysis in tumor cells ( Chen et al, 2018b ), and decreases the pH of the TME ( Balamurugan, 2016 ). Kitajima et al have shown that the disease-specific survival (DSS) of patients with gastric cancer expressing HIF-1 is significantly shorter than that of patients without HIF-1 expression ( Kitajima & Miyazaki, 2013 ).…”

Section: Survey Methodologymentioning

confidence: 99%

The regulation of immune checkpoints by the hypoxic tumor microenvironment

et al. 2021

PeerJ

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The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

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Section: Survey Methodologymentioning

confidence: 99%

The regulation of immune checkpoints by the hypoxic tumor microenvironment

et al. 2021

PeerJ

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“…Hypoxia can lead to a series of pathological processes and cause anomalous changes in tissues and organs with respect to metabolism, function, and morphological structure [ 1 – 3 ]; As an upstream mediator of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1α) is a significant transcription factor for cellular response in hypoxia, and also promotes angiogenesis and boosts metabolism, thus provoking abnormal vascularization [ 4 – 6 ]. However, the fate of this protein is mainly determined by the O2/PHD/pVHL pathway, which is responsible for its ubiquitination and degradation [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function

Dong

Lin

et al. 2021

Cell Commun Signal

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Background Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1α, the transcriptional activator of VEGF, has intricate mechanisms of nuclear translocation and activation, but its signal termination mechanisms remain unclear. Methods We investigated the role of polypyrimidine tract-binding protein-associated splicing factor (PSF) in cellular energy production, migration, and proliferation by targeting HIF-1α in vivo and in vitro PSF plasmids were transfected with liposome 2000 transfection reagent. Young C57/BL6J mice were kept in a hyperoxia environment, followed by indoor air, resulting in oxygen-induced retinopathy. Oxygen-induced retinopathy (OIR) animals were randomly divided into three groups: OIR group, OIR + vector group (OIR cubs treated with rAAV vector) and OIR + PSF group (OIR cubs treated with rAAV-PSF). Age-matched C57/BL6J mice were used as controls and exposed to constant normoxic conditions. The animals were executed and their pupils were subjected to subsequent experiments. The metabolic spectrum was analyzed by Seahorse XFe96 flux analyzer, and OCR and extracellular acidification rate were quantified at the same time. Results PSF ameliorated retinal neovascularization and corrected abnormal VEGF expression in mice with oxygen-induced retinopathy and reduced intra-retinal neovascularization in Vldlr − / − mice. PSF reprogrammed mitochondrial bioenergetics and inhibited the transition of endothelial cells after hypoxia, suggesting its involvement in pathological angiogenesis.Ectopic PSF expression inhibited hypoxia-induced HIF-1α activation in the nucleus by recruiting Hakai to the PSF/HIF-1α complex, causing HIF-1α inhibition. PSF knockdown increased hypoxia-stimulated HIF-1α reactions. These hypoxia-dependent processes may play a vital role in cell metabolism, migration, and proliferation. Thus, PSF is a potential treatment target in neovascularization-associated ophthalmopathy. Conclusion This is the first study showing that PSF inhibits HIF-1α via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 α/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy. PSF-Hakai–HIF-1α signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai–HIF-1α signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1α signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually.

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“…USP28 belongs to the USP deubiquitinase subfamily and plays crucial roles in maintaining the stability of multiple cancer‐related substrate proteins including c‐Myc, LSD1, HIF‐1α, c‐Jun, and Notch [13–15,34–38,52]. Due to its function in controlling the cellular homeostasis of cancer‐related proteins, USP28 has emerged as a potential target for anticancer drug development [7,13].…”

Section: Discussionmentioning

confidence: 99%

USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines

et al. 2020

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Deubiquitinase USP28 plays a crucial role in tumorigenesis by enhancing the stabilities of multiple cancer‐related proteins including c‐Myc, Notch1, and LSD1, and has become an attractive target for anticancer drug development. However, to date, only a few of USP28‐targeted active compounds have been developed, and the active compound‐binding pocket in USP28 has not been experimentally revealed yet. In this study, bioassay‐based high‐throughput screening was applied to discover USP28‐targeted inhibitors from the commercially available drug library. Vismodegib, an inhibitor of Hedgehog signaling pathway and FDA‐approved drug for the treatment of basal cell carcinoma, was found to exhibit inhibition activity against USP28 (IC50: 4.41 ± 1.08 μm). Multiple biophysical and biochemical techniques including NMR, ITC, thermal shift assay, HDX‐MS, and site‐directed mutagenesis analysis were then used to characterize the interaction between Vismodegib and USP28. The binding pocket in USP28 for Vismodegib, which is mainly composed of two helical structures spanning D255‐N278 and N286‐Y293, was revealed. According to the possible binding pose generated by HDX‐MS data‐defined molecular docking, the binding cavity occupied by Vismodegib in USP28 aligns well with one of the reported‐binding pockets in USP7 for its inhibitors. Furthermore, cellular assays were conducted to confirm that Vismodegib could interact with the evolutionarily related deubiquitinases USP28 and USP25 and downregulate the levels of the two enzymes' substrate proteins c‐Myc, Notch1, and Tankyrase‐1/2.

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SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response

Cited by 28 publications

References 19 publications

The regulation of immune checkpoints by the hypoxic tumor microenvironment

The regulation of immune checkpoints by the hypoxic tumor microenvironment

PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function

USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines

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