Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-β-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma

Borgas, Diana; Gao, Jinsong; Tong, Ming

doi:10.1159/000367731

Cited by 8 publications

(16 citation statements)

References 38 publications

(65 reference statements)

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“…In previous publications, the MO-I small molecule inhibitors were demonstrated to target ASPH’s catalytic (hydroxylase) activity and inhibiting cell motility [7, 15, 16]. In addition, a number of publications have documented that mutation of ASPH’s catalytic domain [9, 33] inhibits cell motility in a broad range of malignant neoplastic cells. Furthermore, as demonstrated in the present work, GBM cells transduced with Lenti-sh-ASPH resulting in sustained inhibition of ASPH expression, exhibited reduced viability and directional motility.…”

Section: Discussionmentioning

confidence: 99%

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Sturla

Tong

Hebda

et al. 2016

Heliyon

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BackgroundDespite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM’s highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1α), NOTCH, and aspartate-β-hydroxylase (ASPH).MethodsHuman astrocytoma biopsy specimens (n = 37), WHO Grades II–IV, were analyzed for levels and distributions of ASPH and HIF-1α immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1α mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPH’s catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM.ResultsThe highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1α, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1α. In vitro experiments demonstrated that small molecule inhibitors targeting ASPH’s catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct.ConclusionThis study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH.

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Section: Discussionmentioning

confidence: 99%

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Sturla

Tong

Hebda

et al. 2016

Heliyon

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“…Failure to properly treat AIH and DILI could result in clinically devastating acute or chronic outcomes [5,6] . Chronic AIH could also lead to hepatocarcinogenesis in the future [9][10][11] .…”

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confidence: 99%

Clinicopathological Study of Autoimmune Hepatitis Cases That Were Difficult to Differentiate from Drug-Induced Liver Injury

Tsutsui¹,

Harada²,

Tsuneyama³

et al. 2017

Dig Dis

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Aim: Acute-onset autoimmune hepatitis (AIH) histopathologically presents with features of acute hepatitis and lacks a specific diagnostic method. Also, AIH is often difficult to differentiate from drug-induced liver injury (DILI). We aimed to investigate the final clinical diagnosis of these cases, and compare the clinical, biochemical, and histological characteristics of AIH vs. DILI. Methods: We examined the Digestive Disease Week Japan 2004 (DDW-J) scale scores, AIH scores, clinical data, and pathological findings in 20 patients in whom it was difficult to differentiate autoimmune liver disease from DILI. Results: In cases with a DDW-J scale score of ≥5, there was a good correlation between the final diagnosis and DDW-J scale assessments, but in cases with a DDW-J scale score of ≦4 they did not correlate well. The scores for pathological findings, such as cobblestone hepatocellular change (p = 0.015), interface hepatitis (p = 0.012), and prominent plasma cells in portal areas (p = 0.011), were higher in the AIH group than in the DILI group. Conclusion: This study showed that DDW-J scale was useful for differentiating AIH from DILI in cases with a DDW-J scale score of ≧5. The histologic features of AIH were characterized by cobblestone hepatocellular change, interface hepatitis, and plasma cell infiltration of the portal region.

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“…For example, treatment with chemical inhibitors or siRNA targeting GSK-3β increases ASPH protein expression and cell motility, whereas increasing GSK-3β activity decreases ASPH protein expression and cell migration [8,10,33]. However, those studies do not inform as to whether the effects of GSK-3β are indirect or direct, yet studies showing that ASPH can be phosphorylated [8,26,33,34] support the concept that kinases can phosphorylate ASPH and thereby modulate its expression and function. Furthermore, the notion that ASPH undergoes post-translational modification is supported by its ~140 kD size on SDS-PAGE versus the predicted Mr ~86 kD.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies documented that increasing GSK- 3β activity inhibits ASPH expression and cell motility, whereas inhibiting GSK-3β enhances ASPH protein expression and cell motility [8,26,34]. The additional proposed method of post-transcriptional regulation of ASPH is via direct phosphorylation of the protein by GSK-3β, CK2, PKA, or PKC as diagramed based on the predicted phosphorylation sites (Figure 1B) [8,33].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, post-transcriptional regulation of ASPH can be mediated by trophic factor stimulation such as with insulin or IGF-1, or modulating GSK-3β activity by other mechanisms such as oxidative stress. In a previous study using hepatocellular carcinoma cells, we demonstrated that increased ASPH protein expression and translocation to the plasma membrane enables its C-terminal catalytic domain to interact with and hydroxylate Notch [11,34]. Attendant cleavage of Notch liberates its intracellular domain which enters the nucleus to activate the CSL complex and initiate transcription of Notch signaling target genes HES and HEY and promotes cell motility [33,35].…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation Modulates Aspartyl-(Asparaginyl)-β- Hydroxylase Protein Expression, Catalytic Activity and Migration in Human Immature Neuronal Cerebellar Cells

2017

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Background Abundant aspartyl-asparaginyl-β-hydroxylase (ASPH) expression supports robust neuronal migration during development, and reduced ASPH expression and function, as occur in fetal alcohol spectrum disorder, impair cerebellar neuron migration. ASPH mediates its effects on cell migration via hydroxylation-dependent activation of Notch signaling networks. Insulin and Insulin-like growth factor (IGF-1) stimulate ASPH mRNA transcription and enhance ASPH protein expression by inhibiting Glycogen Synthase Kinase–3β (GSK-3β). This study examines the role of direct GSK-3β phosphorylation as a modulator of ASPH protein expression and function in human cerebellar-derived PNET2 cells. Methods Predicted phosphorylation sites encoded by human ASPH were ablated by S/T→A site-directed mutagenesis of an N-Myc-tagged wildtype (WT) cDNA regulated by a CMV promoter. Phenotypic and functional features were assessed in transiently transfected PNET2 cells. Results Cells transfected with WT ASPH had increased ASPH protein expression, directional motility, Notch-1 and Jagged-1 expression, and catalytic activity relative to control. Although most single- and multi-point ASPH mutants also had increased ASPH protein expression, their effects on Notch and Jagged expression, directional motility and adhesion, and catalytic activity varied such that only a few of the cDNA constructs conferred functional advantages over WT. Immunofluorescence studies showed that ASPH phosphorylation site deletions can alter the subcellular distribution of ASPH and therefore its potential interactions with Notch/Jagged at the cell surface. Conclusions Inhibition of ASPH phosphorylation enhances ASPH protein expression, but attendant alterations in intra-cellular trafficking may govern the functional consequences in relation to neuronal migration, adhesion and Notch activated signaling.

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Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-β-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma

Cited by 8 publications

References 38 publications

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Clinicopathological Study of Autoimmune Hepatitis Cases That Were Difficult to Differentiate from Drug-Induced Liver Injury

Phosphorylation Modulates Aspartyl-(Asparaginyl)-β- Hydroxylase Protein Expression, Catalytic Activity and Migration in Human Immature Neuronal Cerebellar Cells

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