Targeting UDP‐glucose dehydrogenase inhibits ovarian cancer growth and metastasis

Lin, Li‐Hsun; Chou, Hsiu‐Chuan; Chang, Shing‐Jyh; Liao, En‐Chi; Tsai, Yi‐Ting; Wei, Yu‐Shan; Chen, Hsin‐Yi; Lin, Ming-Tzer; Wang, Yi‐Shiuan; Chien, Yu‐An; Yu, Xinru; Chan, Hong‐Lin

doi:10.1111/jcmm.15808

Cited by 18 publications

(31 citation statements)

References 49 publications

(105 reference statements)

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“…Recent studies have reported that UGDH affects patient survival [ 34 ], cell proliferation [ 32 , 37 ], cell invasion [ 27 ], cell migration [ 34 , 37 ] and SNAI1 expression [ 28 ]. We set out to confirm these effects of UGDH in our EMT cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a growing number of studies have focused on UGDH in cancer, and the roles of UGDH in tumour growth, metastasis and patient survival have been well documented [27,32,[34][35][36][37]. Additionally, UGDH has been connected to EMT [27,28,32,34,75]. Arnold et al [27] reported that UGDH was highly expressed in mesenchymal cells and mesenchymal-like breast cancers and connected UDP-GlcA (the enzymatic product of UGDH) to extracellular matrix remodelling and mesenchymal-like properties.…”

Section: Discussionmentioning

confidence: 99%

“…(I) The enzyme PLA2G15 potentially involved in the hydrolysis of phosphatidylcholine (PtdCho) into GPC was higher in both D492M and D492HER2. UGDH has been reported to regulate the phosphorylation of ERK (pERK) [32]. cPLA2 is responsible for GPC synthesis from PtdCho in choline metabolism and is under the control of ERK/MAPK [89,90].…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…UGDH is involved in a variety of regulatory events. SP1, TGF‐β, Slit2, p38 MAPK and PI3K/Akt regulate UGDH expression, which in turn influences the downstream targets ERK/MAPK, PPARγ and SNAI1 [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Several studies have recently reported that UGDH is involved in tumour growth, metastasis and patient survival [ 27 , 32 , 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

“…SP1, TGF‐β, Slit2, p38 MAPK and PI3K/Akt regulate UGDH expression, which in turn influences the downstream targets ERK/MAPK, PPARγ and SNAI1 [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Several studies have recently reported that UGDH is involved in tumour growth, metastasis and patient survival [ 27 , 32 , 34 , 35 , 36 , 37 ]. To understand the roles of UGDH in EMT in the breast gland, we knocked down UGDH in breast mesenchymal cells with siRNAs and studied effects on cell function and metabolism.…”

Section: Introductionmentioning

confidence: 99%

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UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

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Metabolic rewiring is one of the indispensable drivers of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomic approach supported by metabolomic analysis. We identified common proteomic changes, including the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included the following: FDFT1, SORD, TSTA3 and UDP‐glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA‐mediated knock‐down of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA‐mediated knock‐down of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet‐derived growth factor receptor beta (PDGFRB) signalling was activated in mesenchymal cells. siRNA‐mediated knock‐down of PDGFRB downregulated UGDH expression, potentially via NFkB‐p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Conflict Of Interestmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

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BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer

Fan,

Pan,

Jia

et al. 2023

Cancer Medicine

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Cisplatin‐based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat‐containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti‐apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin‐resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6‐methyladenosine (m6A) binding sites. The modification of m6A was found to enhance the expression of BIRC5 by recognizing and binding to the 3′‐UTR of mRNA. Additionally, the insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co‐silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m6A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.

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Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFβ signalling pathway

Gao

Cheng

Chang

et al. 2022

Clinical & Translational Med

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1. UDP-glucose 6-dehydrogenase (UGDH)-mediated UDP-GlcUA accumulation promotes hepatoma cell migration upon GSTZ1 loss. 2. UDP-GlcUA stabilized TGFβR1 mRNA by enhancing its binding to PTBP3, contributing to the activation of TGFβ/Smad signalling. 3. UGDH and a key intermediate metabolite, UDP-GlcUA are strong predictors of an increased risk of HCC metastasis, and targeting UGDH might be a promising strategy for HCC therapy.

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Targeting UDP‐glucose dehydrogenase inhibits ovarian cancer growth and metastasis

Cited by 18 publications

References 49 publications

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer

Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFβ signalling pathway

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Targeting UDP‐glucose dehydrogenase inhibits ovarian cancer growth and metastasis

Cited by 18 publications

References 49 publications

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

BIRC5 facilitates cisplatin‐chemoresistance in a m6A‐dependent manner in ovarian cancer

Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFβ signalling pathway

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BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer