Aspartate β-hydroxylase as a target for cancer therapy

Kanwal, Madiha; Šmahel, Michal; Olsen, Mark; Smahelova, Jana; Tachezy, Ruth

doi:10.1186/s13046-020-01669-w

Cited by 45 publications

(55 citation statements)

References 103 publications

(174 reference statements)

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“…We constructed the risk signature using the 12 genes. Among them, aspartate β-hydroxylase (ASPH) plays a pivotal role in the malignant transformation of solid tumors by enhancing cell proliferation, migration, invasion and stimulation of angiogenesis, and immunosuppression (Ince et al, 2000;Huyan et al, 2014;Kanwal et al, 2020). A previous study showed that repression of aldehyde dehydrogenase 2 family (ALDH2) promotes lung tumor progression through accumulated acetaldehyde and DNA damage (Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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Background: Lung cancer has emerged as one of the most common cancers in recent years. The mitochondrial electron transport chain (ETC) is closely connected with metabolic pathways and inflammatory response. However, the influence of ETC-associated genes on the tumor immune response and the pathogenesis of lung cancer is not clear and needs further exploration.Methods: The RNA-sequencing transcriptome and clinical characteristic data of LUAD were downloaded from the Cancer Genome Atlas (TCGA) database. The LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve. We explored the function of FDX1 through flow cytometry, molecular biological methods, and liquid chromatography–tandem mass spectrometry/mass spectrometry (LC–MS/MS).Results: 12 genes (FDX1, FDX2, LOXL2, ASPH, GLRX2, ALDH2, CYCS, AKR1A1, MAOB, RDH16, CYBB, and CYB5A) were selected to build the risk signature, and the risk score was calculated with the coefficients from the LASSO algorithm. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves of the dataset were 0.7, 0.674, and 0.692, respectively. Univariate Cox analysis and multivariate Cox regression analysis indicated that the risk signature is an independent risk factor for LUAD patients. Among these genes, we focused on the FDX1 gene, and we found that knockdown of FDX1 neither inhibited tumor cell growth nor did it induce apoptosis or abnormal cell cycle distribution. But FDX1 could promote the ATP production. Furthermore, our study showed that FDX1 was closely related to the glucose metabolism, fatty acid oxidation, and amino acid metabolism.Conclusion: Collectively, this study provides new clues about carcinogenesis induced by ETC-associated genes in LUAD and paves the way for finding potential targets of LUAD.

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Section: Discussionmentioning

confidence: 99%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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“…Further, considering the pleiotropic effects that NOG and its derivatives exhibit in cellular studies, application of related 2-oxo acid derivatives to cells may trigger phenotypes useful in identifying previously overlooked 2OG oxygenase/2OG-utilizing enzyme functions. FIH 76 and AspH 22 – 26 are proposed medicinal chemistry targets and the use of (partially) selective 2OG derivatives, such as 13 or corresponding esters in cellular studies may help to improve the currently limited understanding on their biochemical roles and complement similar approaches using heterocyclic small-molecules 24 , 76 – 81 .…”

Section: Discussionmentioning

confidence: 99%

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

et al. 2021

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Abstract2-Oxoglutarate (2OG) oxygenases are validated agrochemical and human drug targets. The potential for modulating their activity with 2OG derivatives has not been explored, possibly due to concerns regarding selectivity. We report proof-of-principle studies demonstrating selective enhancement or inhibition of 2OG oxygenase activity by 2-oxo acids. The human 2OG oxygenases studied, factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH) and aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations of Asp/Asn-residues. Of 35 tested 2OG derivatives, 10 enhance and 17 inhibit FIH activity. Comparison with results for AspH reveals that 2OG derivatives selectively enhance or inhibit FIH or AspH. Comparison of FIH structures complexed with 2OG derivatives to those for AspH provides insight into the basis of the observed selectivity. 2-Oxo acid derivatives have potential as drugs, for use in biomimetic catalysis, and in functional studies. The results suggest that the in vivo activity of 2OG oxygenases may be regulated by natural 2-oxo acids other than 2OG.

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“…S4C and S4D), suggesting INPP5F may affect the function of ASPH. Previous reports showed that the Notch pathway is a downstream signaling of ASPH [20,21]. Coincidentally, c-MYC and cyclin E1 are important targets of the Notch signaling pathway [22,23].…”

Section: Inpp5f Activates Notch Signaling Pathway Via Interacting With Asphmentioning

confidence: 97%

INPP5F Translocates Into Cytoplasm And Interacts With ASPH To Promote Tumor Growth in Hepatocellular Carcinoma

Zhou

Lin

Yan

et al. 2021

Preprint

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Background: Increasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression. However, the role of INPP5F in hepatocellular carcinoma (HCC) and its underlying mechanisms is unclear.Methods: The expression of INPP5F in HCC was analyzed in public databases and our clinical specimens. The biological functions of INPP5F were investigated in vitro and vivo. The molecular mechanism of INPP5F in regulating tumor growth were studied by transcriptome-sequencing analysis, mass spectrometry analysis, immunoprecipitation assay and immunofluorescence assay.Results: High expression of INPP5F was found in HCC tissues and was associated with poor prognosis in HCC patients. Overexpression of INPP5F promoted HCC cell proliferation, and vice versa. Knockdown of INPP5F suppressed tumor growth in vivo. Results from transcriptome-sequencing analysis showed INPP5F not only regulated a series of cell cycle related genes expression (c-MYC and cyclin E1), but also promoted many aerobic glycolysis related genes expression. Further studies confirmed that INPP5F could enhance lactate production and glucose consumption in HCC cell. Mechanistically, INPP5F activated Notch signaling pathway and upregulated c-MYC and cyclin E1 in HCC via interacting with ASPH. Interestingly, INPP5F was commonly nuclear-located in cells of adjacent non-tumor tissues, while in HCC, cytoplasm-located was more common. LMB (nuclear export inhibitor) treatment restricted INPP5F in nucleus and was associated with inhibition of Notch signaling and cell proliferation. Sequence of nuclear localization signals (NLSs) and nuclear export signals (NESs) in INPP5F aminoacidic sequence were then identified. Alteration of the NLSs or NESs influenced the localization of INPP5F and the expression of its downstream molecules. Furthermore, we found INPP5F interacted with both exportin and importin through NESs and NLSs, respectively, but the interaction with exportin was stronger, leading to cytoplasmic localization of INPP5F in HCC. Conclusion: These findings indicate that INPP5F functions as an oncogene in HCC via a translocation mechanism and activating ASPH-mediated Notch signaling pathway. INPP5F may serve as a potential therapeutic target for HCC patients.

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Aspartate β-hydroxylase as a target for cancer therapy

Cited by 45 publications

References 103 publications

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

INPP5F Translocates Into Cytoplasm And Interacts With ASPH To Promote Tumor Growth in Hepatocellular Carcinoma

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