Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM)

Baryła, Izabela; Płuciennik, Elżbieta; Kośla, Katarzyna; Wójcik, Marzena; Zieleniak, Andrzej; Źurawska-Kliś, Monika; Cypryk, Katarzyna; Woźniak, Lucyna A.

doi:10.7717/peerj.10604

Cited by 9 publications

(18 citation statements)

References 72 publications

(45 reference statements)

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“…As there is growing evidence that mitochondrial superoxide production is dispensable in the pathogenesis of diabetes, it was suggested that stabilization of HIF1α and associated metabolic reprogramming, resembled the Warburg effect, were the initial events in the cellular biochemical abnormalities induced by glucose in diabetes [ 4 , 57 ]. Therefore, the WWOX/HIF1A lowered expression ratio should be considered as a molecular risk factor for diabetes type 2 and gestational as we already reported [ 50 ]. It is worth noting that XIAP, a member of the inhibitors of apoptosis proteins (IAPs) [ 58 ] is a regulator of HIF1α polyubiquitination [ 59 ].…”

Section: Discussionmentioning

confidence: 82%

“…Our previous study suggests a significant contribution of the WWOX gene to glucose metabolism in patients with gestational diabetes mellitus. We showed decreased WWOX expression in GDM compared to normal pregnancy, and what is most important a significant reduction of WWOX/HIF1A ratio [ 50 ]. These results indicated that WWOX modulates HIF1α activity and the effect of HIF1α excessive activation was to increase the expression of genes encoding proteins directly involved in the glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…It might lead to pathological changes in glucose metabolism observed in gestational diabetes. The goal of this study was to analyze the impact of WWOX on glycolysis in hyperglycemia and hypoxia conditions in a human fibroblast cell line, based on an assumption of the importance of the WWOX gene in the pathophysiology of diabetes [ 45 , 47 , 50 , 51 , 52 ]. We determined that knock-out of WWOX leads to increased HIF1A mRNA and protein level together with its translocation to the nucleus and raise of its transactivation function.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study showed decreased WWOX expression and an increase of HIF1A and its targets glycolysis genes in gestational diabetes mellitus (GDM) patients in comparison to control [ 50 ]. These results indicated that WWOX modulates HIF1α activity in GDM patients.…”

Section: Introductionmentioning

confidence: 99%

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The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

Baryła

Styczeń-Binkowska

Płuciennik

et al. 2022

IJMS

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Recent reports indicate that the hypoxia-induced factor (HIF1α) and the Warburg effect play an initiating role in glucotoxicity, which underlies disorders in metabolic diseases. WWOX has been identified as a HIF1α regulator. WWOX downregulation leads to an increased expression of HIF1α target genes encoding glucose transporters and glycolysis’ enzymes. It has been proven in the normoglycemic mice cells and in gestational diabetes patients. The aim of the study was to determine WWOX’s role in glucose metabolism regulation in hyperglycemia and hypoxia to confirm its importance in the development of metabolic disorders. For this purpose, the WWOX gene was silenced in human normal fibroblasts, and then cells were cultured under different sugar and oxygen levels. Thereafter, it was investigated how WWOX silencing alters the genes and proteins expression profile of glucose transporters and glycolysis pathway enzymes, and their activity. In normoxia normoglycemia, higher glycolysis genes expression, their activity, and the lactate concentration were observed in WWOX KO fibroblasts in comparison to control cells. In normoxia hyperglycemia, it was observed a decrease of insulin-dependent glucose uptake and a further increase of lactate. It likely intensifies hyperglycemia condition, which deepen the glucose toxic effect. Then, in hypoxia hyperglycemia, WWOX KO caused weaker glucose uptake and elevated lactate production. In conclusion, the WWOX/HIF1A axis downregulation alters glucose metabolism and probably predispose to metabolic disorders.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

Baryła

Styczeń-Binkowska

Płuciennik

et al. 2022

IJMS

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“…Significant reduction in expression of WW‐domain‐containing oxidoreductase (WWOX) was observed in GDM patients with a simultaneous increase in hypoxia‐inducible factor 1 (HIF1) causing lowering of WWOX/HIF1α ratio. The increase in HIF1α activity causes an increase in the expression of genes involved in glycolysis leading to pathological changes in glucose metabolism as found in the GDM condition [34].…”

Section: Signaling Pathways Involved In the Pathogenesis Of Gdmmentioning

confidence: 99%

An insight into major signaling pathways and protein–protein interaction networks involved in the pathogenesis of gestational diabetes mellitus

Chatterjee

Neelaveni

Kenchey³

et al. 2022

Proteomics

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Gestational diabetes mellitus (GDM) is associated with the increase of glucose in the blood rather than being absorbed by the cells. A better understanding of the signaling pathways is necessary to understand the pathophysiology of GDM. This study provides details about a series of signaling pathways and protein–protein interactions involved in the pathogenesis of GDM and their evaluations in GDM development. Protein–protein interactions were found between proteins of several signaling pathways that suggest interlink between these signaling pathways. Protein–protein interactions were generated with high confidence interaction scores based on textmining, cooccurrence, coexpression, neighborhood, gene fusion, experiments, and databases. The dysregulation of signaling pathways may also contribute to the increased risk of complications associated with GDM in the mother and child. Further, studies on signaling pathways involved in the pathogenesis of GDM would help in the development of an effective intervention to prevent GDM along with the identification of key targets for effective therapies in the future.

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WWOX and metabolic regulation in normal and pathological conditions

Baryła

Kośla

2022

J Mol Med

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WW domain-containing oxidoreductase (WWOX) spans the common fragile site FRA16D. There is evidence that translocations and deletions affecting WWOX accompanied by loss of expression are frequent in many cancers and often correlate with a worse prognosis. Additionally, WWOX germline mutations were also found to be the cause of pathologies of brain development. Because WWOX binds to some transcription factors, it is a modulator of many cellular processes, including metabolic processes. Recently, studies have linked WWOX to familial dyslipidemias, osteopenia, metabolic syndrome, and gestational diabetes, confirming its role as a regulator of steroid, cholesterol, glucose, and normal bone metabolism. The WW domain of WWOX is directly engaged in the control of the activity of transcription factors such as HIF1α and RUNX2; therefore, WWOX gene alterations are associated with some metabolic abnormalities. Presently, most interest is devoted to the associations between WWOX and glucose and basic energy metabolism disturbances. In particular, its involvement in the initiation of the Warburg effect in cancer or gestational diabetes and type II diabetes is of interest. This review is aimed at systematically and comprehensively presenting the current state of knowledge about the participation of WWOX in the metabolism of healthy and diseased organisms.

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Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM)

Cited by 9 publications

References 72 publications

The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

The WWOX/HIF1A Axis Downregulation Alters Glucose Metabolism and Predispose to Metabolic Disorders

An insight into major signaling pathways and protein–protein interaction networks involved in the pathogenesis of gestational diabetes mellitus

WWOX and metabolic regulation in normal and pathological conditions

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