scholarly journals Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

2021 ◽  
Vol 9 ◽  
Author(s):  
Bingluo Zhou ◽  
Yiran Zhu ◽  
Wenxia Xu ◽  
Qiyin Zhou ◽  
Linghui Tan ◽  
...  
Keyword(s):  
Target Genes ◽  
Antiangiogenic Therapy ◽  
Hypoxia Inducible Factor ◽  
Protein Inhibitor ◽  
Hypoxia Response ◽  
Hypoxia Stress ◽  
Lysine Specific Demethylase ◽  
Chemical Inhibition ◽  
Sumo E3 Ligase

Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.

Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles

2013 ◽  
Vol 394 (4) ◽  
pp. 435-448 ◽  
Author(s):  
Johanna Myllyharju ◽  
Peppi Koivunen
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Drug Candidate ◽  
Hypoxia Response ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Biological Studies ◽  
The Common

Abstract Hypoxia-inducible transcription factor (HIF), an αβ dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e.g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells. The oxygen-sensing mechanism behind this phenomenon is provided by HIF prolyl 4-hydroxylases (HIF-P4Hs, commonly known as PHDs and EglNs) that require oxygen in their reaction. In normoxia, two prolines in the oxygen-dependent degradation domain of the HIFα subunit become hydroxylated by the HIF-P4Hs. The 4-hydroxyproline residues formed serve as recognition sites for the von Hippel-Lindau E3 ubiquitin ligase complex and result in subsequent ubiquitination and instant proteasomal degradation of HIFα in normoxia. The HIF-P4H reaction is inhibited in hypoxia. HIFα evades degradation and forms a functional dimer with HIFβ, leading to activation of the HIF target genes. The central role of HIF-P4Hs in the regulation of the hypoxia response pathway has provided an attractive possibility as a drug candidate for treatment of, e.g., severe anemias and ischemic conditions, and several companies are currently carrying out clinical studies on the use of HIF-P4H inhibitors to treat anemia in patients with a kidney disease. Therefore, it is important to understand the effects of individual HIF-P4H isoenzymes on the hypoxia response and potential other pathways in vivo. The common and specific functions of the HIF-P4H isoenzymes are discussed in this review on the basis of available data from cell biological studies and gene-modified animals.

scholarly journals In Vivo Topoisomerase I Inhibition Attenuates the Expression of Hypoxia-Inducible Factor 1α Target Genes and Decreases Tumor Angiogenesis

2011 ◽  
Vol 18 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Eric Guérin ◽  
Wolfgang Raffelsberger ◽  
Erwan Pencreach ◽  
Armin Maier ◽  
Agnès Neuville ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Topoisomerase I ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling

2007 ◽  
Vol 97 (05) ◽  
pp. 774-787 ◽  
Author(s):  
Norbert Weissmann ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
Frank Rose ◽  
Jörg Hänze
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Ischemic Disease ◽  
Hypoxic Conditions ◽  
Concomitant Reduction ◽  
Adaptive Processes

SummaryHypoxia-inducible factor (HIF) is an oxygen-dependent transcription factor that activates a diverse set of target genes, the products of which are involved in adaptive processes to hypoxia. Employing genetic manipulation of HIF expression, in-vivo and cellular studies have focused on HIF as a crucial factor affecting hypoxia-induced vascular remodeling.Vascular remodeling comprises processes which establish and improve blood vessel supply such as vasculogenesis, angiogenesis and arteriogenesis. These processes are observed during ontogenesis, tumor progression, ischemic disease or physical training. Furthermore, under hypoxic conditions, a pulmonary-specific type of vascular remodeling called pulmonary arterial remodeling occurs that is characterized by thickening of the vessel wall with a concomitant reduction in the vessel lumen area, thereby limiting blood flow.This response results in pulmonary hypertension with right ventricular hypertrophy, a lethal disease. In this review, we summarize and discuss mechanisms by which HIF interferes with the different vascular remodeling processes.

scholarly journals Activation of the Hypoxia-Inducible Factor Pathway Expands Early Thymic Progenitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2896-2896
Author(s):  
Anita Hollenbeck ◽  
Stefanie Weber ◽  
Kathrin Händschke ◽  
Mandy Necke ◽  
Bertram Opalka ◽  
...  
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Cell Receptor ◽  
Normal Numbers ◽  
Cellular Compartment ◽  
Vhl Gene ◽  
Von Hippel Lindau

Abstract Early thymic progenitors enter the thymus and are exposed to regional hypoxia while they develop in a step-wise manner to mature functional T-cells. Therefore, hypoxia might represent an important component of the highly specialized thymic microenvironment. On the molecular level the hypoxia-inducible factor pathway controls the cellular response to hypoxia. In this pathway, the von-Hippel-Lindau protein (pVHL) continuously mediates the destruction of the transcription factor hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. Under hypoxia HIF-1α degradation is inhibited leading to the activation of HIF-1α target genes. Others used lck-Cre transgene-mediated conditional in vivo deletion of the Vhl gene to study the role of the oxygen-sensing pathway in developing thymocytes and found normal numbers of early double-negative (DN; CD4-CD8-) thymocytes (Biju et al., Mol Cell Biol, 2004). However, lck-Cre deletion initiates at the DN3 (CD25+CD44-) stage leaving the Vhl locus of very early DN1 (CD25-CD44+), DN2 (CD25+CD44+) and DN3 thymocytes unaltered. Therefore, we here used the ubiquitous hematopoietic deleter strain vav-Cre to investigate the role of pVHL in very early thymocytes (vav-Cre;VhlloxP;loxP mice). Using a PCR-based strategy we confirmed complete deletion of the Vhl gene in this model. We observed unaltered DN1 and DN2 progenitor numbers, however in contrast to the published lck-cre-mediated system we consistently observed an up to twofold expansion of the DN3 cellular compartment. As the hypoxia-inducible factor pathway was shown to modulate NOTCH1 signaling we studied Notch1 expression on Vhl-deficient thymocytes. Strikingly, Notch1 expression was significantly increased on expanded Vhl null DN3 thymocytes. At the DN3 developmental stage selection of cells with an accurately re-arranged T-cell receptor β-locus occurs. Thus, we analyzed pre- and post-β-selection DN3 cells by CD28 staining. Interestingly, we found both pre- and post-β-selection DN3 subpopulations expanded. In order to investigate whether the progenitor expansion is mediated by the lack of HIF-1α inhibition in the Vhl-deficient context we studied DN3 thymocytes in a conditional hematopoietic HIF-1α gain-of-function model (vav-Cre;HIF1dPA). Overexpression of HIF-1α, which is insensitive to pVHL-mediated degradation in vav-Cre;HIF1dPAmice, also resulted in expanded DN3 thymocytes. In summary, we describe novel conditional models to genetically alter the hypoxia-inducible factor pathway within very early thymic progenitors. Genetic Vhl loss led to an expansion of DN3 thymocytes. This DN3 expansion is most likely due to the absence of HIF-1α-inhibition, because HIF-1α overexpression phenocopied the Vhl-deficient DN3 thymocyte expansion. Disclosures Dührsen: Celgene: Honoraria, Research Funding.

An Update of Lysine Specific Demethylase 1 Inhibitor: A Patent Review (2016-2020)

2021 ◽  
Vol 16 ◽  
Author(s):  
Yi-Chao Zheng ◽  
Yue-Jiao Liu ◽  
Ya Gao ◽  
Bo Wang ◽  
Hong-Min Liu
Keyword(s):  
Natural Products ◽  
Target Genes ◽  
Flavin Adenine Dinucleotide ◽  
Structural Diversity ◽  
Clinical Phase ◽  
Lysine Specific Demethylase ◽  
Patent Review ◽  
Anti Cancer

Background: As a FAD (Flavin Adenine Dinucleotide) - dependent histone demethylase discovered in 2004, LSD1 (lysine specific demethylase 1) was reported to be overexpressed in diverse tumors, regulating target genes transcription associated with cancer development. Hence, LSD1 targeted inhibitors may represent a new insight in anticancer drug discovery. For these reasons, researchers in both the pharmaceutical industry and academia have been actively pursuing LSD1 inhibitors in the quest for new anti-cancer drugs. Objectives: This review summaries patents about LSD1 inhibitors in recent 5 years in hope of providing a reference for LSD1 researchers to develop new modulators of LSD1 with higher potency and fewer adverse effects. Methods: This review collects LSD1 inhibitors disclosed in patents since 2016. The primary ways of patent searching are Espacenet®, Google Patents, and CNKI. Results: This review covers dozens of patents related to LSD1 inhibitors in recent five years. The compound structures are mainly divided into TCP (Tranylcypromine) derivatives, imidazole derivatives, pyrimidine derivatives, and other natural products and peptides. Meanwhile, the compounds that have entered the clinical phase are also described. Conclusion: Most of the compounds in these patents have been subjected to activity analysis with LSD1 and multi-cell lines, showing good antitumor activity in vitro and in vivo. These patents exhibited the structural diversity of LSD1 inhibitors and the potential of natural products as novel LSD1 inhibitors.

scholarly journals Activation of Hypoxia Response in Endothelial Cells Contributes to Ischemic Cardioprotection

2013 ◽  
Vol 33 (16) ◽  
pp. 3321-3329 ◽  
Author(s):  
Risto Kerkelä ◽  
Sara Karsikas ◽  
Zoltan Szabo ◽  
Raisa Serpi ◽  
Johanna Magga ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Small Molecule ◽  
Target Genes ◽  
Systolic Function ◽  
Hypoxia Inducible Factor ◽  
Wild Type ◽  
Hypoxia Response ◽  
Lv Systolic Function ◽  
Collateral Vessels ◽  
Endothelial Nitric Oxide

Small-molecule inhibition of hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) is being explored for the treatment of anemia. Previous studies have suggested that HIF-P4H-2 inhibition may also protect the heart from an ischemic insult.Hif-p4h-2gt/gtmice, which have 76 to 93% knockdown ofHif-p4h-2mRNA in endothelial cells, fibroblasts, and cardiomyocytes and normoxic stabilization of Hif-α, were subjected to ligation of the left anterior descending coronary artery (LAD). Hif-p4h-2 deficiency resulted in increased survival, better-preserved left ventricle (LV) systolic function, and a smaller infarct size. Surprisingly, a significantly larger area of the LV remained perfused during LAD ligation inHif-p4h-2gt/gthearts than in wild-type hearts. However, no difference was observed in collateral vessels, while the size of capillaries, but not their number, was significantly greater inHif-p4h-2gt/gthearts than in wild-type hearts.Hif-p4h-2gt/gtmice showed increased cardiac expression of endothelial Hif target genes for Tie-2, apelin, APJ, and endothelial nitric oxide (NO) synthase (eNOS) and increased serum NO concentrations. Remarkably, blockage of Tie-2 signaling was sufficient to normalize cardiac apelin and APJ expression and resulted in reversal of the enlarged-capillary phenotype and ischemic cardioprotection inHif-p4h-2gt/gthearts. Activation of the hypoxia response by HIF-P4H-2 inhibition in endothelial cells appears to be a major determinant of ischemic cardioprotection and justifies the exploration of systemic small-molecule HIF-P4H-2 inhibitors for ischemic heart disease.

scholarly journals Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryoichi Bessho ◽  
Yumi Takiyama ◽  
Takao Takiyama ◽  
Hiroya Kitsunai ◽  
Yasutaka Takeda ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Oxygen Consumption ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Sglt2 Inhibitor ◽  
Inhibitory Effect ◽  
Sglt2 Inhibitors ◽  
Proximal Tubular Epithelial Cells ◽  
Renal Proximal Tubular

Abstract Previous studies have demonstrated intrarenal hypoxia in patients with diabetes. Hypoxia-inducible factor (HIF)-1 plays an important role in hypoxia-induced tubulointerstitial fibrosis. Recent clinical trials have confirmed the renoprotective action of SGLT2 inhibitors in diabetic nephropathy. We explored the effects of an SGLT2 inhibitor, luseogliflozin on HIF-1α expression in human renal proximal tubular epithelial cells (HRPTECs). Luseogliflozin significantly inhibited hypoxia-induced HIF-1α protein expression in HRPTECs. In addition, luseogliflozin inhibited hypoxia-induced the expression of the HIF-1α target genes PAI-1, VEGF, GLUT1, HK2 and PKM. Although luseogliflozin increased phosphorylated-AMP-activated protein kinase α (p-AMPKα) levels, the AMPK activator AICAR did not changed hypoxia-induced HIF-1α expression. Luseogliflozin suppressed the oxygen consumption rate in HRPTECs, and subsequently decreased hypoxia-sensitive dye, pimonidazole staining under hypoxia, suggesting that luseogliflozin promoted the degradation of HIF-1α protein by redistribution of intracellular oxygen. To confirm the inhibitory effect of luseogliflozin on hypoxia-induced HIF-1α protein in vivo, we treated male diabetic db/db mice with luseogliflozin for 8 to 16 weeks. Luseogliflozin attenuated cortical tubular HIF-1α expression, tubular injury and interstitial fibronectin in db/db mice. Together, luseogliflozin inhibits hypoxia-induced HIF-1α accumulation by suppressing mitochondrial oxygen consumption. The SGLT2 inhibitors may protect diabetic kidneys by therapeutically targeting HIF-1α protein.

scholarly journals LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium

2021 ◽  
Vol 22 (12) ◽  
pp. 6581
Author(s):  
Sujin Ju ◽  
Leejin Lim ◽  
Kwanhwan Wi ◽  
Changwon Park ◽  
Young-Jae Ki ◽  
...  
Keyword(s):  
Target Genes ◽  
Apoptotic Cell ◽  
Low Density Lipoprotein ◽  
Hypoxia Inducible Factor ◽  
Density Lipoprotein ◽  
Ischemic Myocardium ◽  
Negative Regulator ◽  
Hypoxic Conditions ◽  
Density Lipoprotein Receptor

Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/β-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/β-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.

scholarly journals Hypoxia stimulates SUMOylation-dependent stabilization of KDM5B

2021 ◽  
Author(s):  
Bingluo Zhou ◽  
Yiran Zhu ◽  
Wenxia Xu ◽  
Qiyin Zhou ◽  
Linghui Tan ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Tumor Hypoxia ◽  
Protein Stabilization ◽  
Tumor Xenograft ◽  
Cyclin Dependent Kinase ◽  
Normal Tissues ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Lysine Specific Demethylase

Abstract Background Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress through activating a series of adaption response. The study on the mechanism of tumor hypoxia adaption is still of urgent significance to find effective therapeutic targets and strategies. Methods We compared the protein expression of KDM5B in tumor or normal tissues and cell lines by IHC and Western blotting (WB). CCK8 and cell colony formation assay was performed to evaluate the KDM5B caused growth inhibition. The transcriptome analysis, quantitative real-time PCR (qPCR), flow cytometry analysis, chromatin immunoprecipitation (ChIP) were for exploring the downstream mechanism. And the SUMOylation assay and Ni-beads pull-down assay and co-immunoprecipitation (co-IP) were used to illustrate how did post-translation modification (PTM) regulate the KDM5B protein stabilization. Finally, tumor xenograft assay in nude mice verified the findings in vivo. Results We found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia condition. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Inhibition of KDM5B caused significant cell cycle G1/S arrest through the transcription upregulation of cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21). Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase which increased the interaction with KDM5B under hypoxia condition. As the result, co-targeting KDM5B significantly improved the anti-tumor efficacy of antiangiogenic therapy in vivo. Conclusion Taken together, PIAS4 mediated SUMOylation stabilized KDM5B protein through disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia adaption. Targeting SUMOylation-dependent KDM5B upregulation might be considered when antiangiogenic therapy was applied in cancer treatment.

Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13543-e13543 ◽  
Author(s):  
Tamara Maes ◽  
Iñigo Tirapu ◽  
Cristina Mascaró ◽  
Alberto Ortega ◽  
Angels Estiarte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Computational Models ◽  
Target Genes ◽  
Differentiation Markers ◽  
Enantiomerically Pure ◽  
Lysine Specific Demethylase ◽  
Histone Modifiers ◽  
Differentiation Block

e13543 Background: The lysine-specific demethylase KDM1A catalyzes the removal of methyl groups from mono and dimethylated H3K4/K9, changes that have inductive or inhibitory effects on gene expression. KDM1A is a key regulator of leukemia stem cell (LSC) potential and is required for MLL-AF9 oncogenic transformation. Inhibition of KDM1A expression or activity overcomes the differentiation block in AML. Mixed lineage leukemia (MLL) is a form of AML that is especially sensitive to inhibition of KDM1A. Methods: Gene expression was analyzed using microarrays, cell differentiation was assessed by FACS, viability and apoptosis were assessed by MTT assay and PI staining, me2H3K4 levels were quantified by qPCR and ChIPseq. Results: We used computational models based on reported X-ray structures fine-tuned with the SAR of a first series of molecules to design and synthesize >800 KDM1A inhibitors. ORY-1001 is an enantiomerically pure KDM1A inhibitor (IC50 <20nM) with high selectivity against related FAD dependent aminoxidases (MAO-A/B, IL4I1, KDM1B >100uM, SMOX 7uM). ORY-1001 does not inhibit non-related histone modifiers, and is clean in a CEREP diversity panel. Treatment of THP-1 (MLL-AF9) cells with ORY-1001, results in a time/dose dependent me2H3K4 accumulation at KDM1A target genes and concomitant induction of differentiation markers (EC50 me2H3K4 and FACS CD11b <1nM). Microarray analysis of treated THP-1 cells reveals differentiation towards a monocyte-like phenotype. ORY-1001 induces apoptosis in THP-1 and inhibits proliferation and colony formation of MV(4;11) (MLL-AF4) cells (EC50 <1nM). Daily oral administration of doses <0.020mg/kg leads to significantly reduced tumor growth in rodent MV(4;11) xenografts. In vivo and in vitro IND/IMPD enabling studies have shown that ORY-1001 presents excellent oral bioavailability, target exposure and activity in vivo. The compound is stable in hepatocytes (Clint<0.6 mL/min/g liver, @1uM) and does not exhibit CYP (IC50>100uM) or hERG (%inhib.<2%, @10uM) inhibition. No off-target activity has been detected in 28d rat toxicology studies. Conclusions: A potent and selective KDM1A inhibitor is described with in vitro and vivo anti-leukemic efficacy.

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