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Review Open Access

O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review)

  • Authors:
    • Purin Charoensuksai
    • Siwanon Jirawatnotai
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    Affiliations: Department of Biomedicine and Health Informatics, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand, Siriraj Center of Research Excellence for Precision Medicine and Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
    Copyright: © Charoensuksai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 119
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    Published online on: July 18, 2025
       https://doi.org/10.3892/or.2025.8952
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Abstract

Aberrant O‑GlcNAcylation and the upregulation of O‑GlcNAc transferase (OGT) are key contributors to cancer pathogenesis and progression, driving hyperproliferative states and metastatic phenotypes. Targeting OGT may suppress cancer progression, positioning OGT and O‑GlcNAc signaling as compelling targets in cancer research. Cholangiocarcinoma (CCA), a rare yet highly aggressive malignancy of the bile duct system, represents a clinical challenge, underscored by its rising global mortality, poor survival outcomes and high recurrence rate, despite advances in awareness, diagnostics and therapeutic strategies. Consequently, there is need for novel therapeutic modalities. Hyperactive O‑GlcNAcylation and upregulation of OGT are observed in CCA, therefore, targeting protein O‑GlcNAcylation may have clinical potential. The present review aimed to summarize the impact of O‑GlcNAcylation on CCA and CCA‑relevant hallmarks of cancer including cell proliferation, metastasis, metabolic reprogramming, angiogenesis, programmed cell death and tumor‑associated inflammation. In areas where direct evidence in CCA is limited, insights from other gastrointestinal tract cancers may identify potential mechanistic connections, offering a broader context to guide future investigation. Furthermore, the viability of OGT and O‑GlcNAcylation as therapeutic targets is discussed.
View Figures

Figure 1

Schematic diagram of OGT gene and
protein structure. (A) Genomic location of the human OGT gene on
the X chromosome containing 23 exons (green). (B) Protein domain
organization of the three OGT isoforms depicting TPR, NLS,
catalytic region comprising Cat-1 and Cat-2. The mOGT isoform
uniquely features a MTS at its N-terminus. Amino acid numbers
marking the boundaries of each domain are also indicated. (C) 3D
structure of ncOGT protein. Image retrieved from
genecards.org/cgi-bin/carddisp.pl?gene=OGT. mOGT, mitochondrial
O-GlcNAc transferase TPR, tetratricopeptide repeat; NLS, nuclear
localization sequence; Cat, catalytic region; MTS, mitochondrial
targeting sequence; nc, nucleocytoplasmic; s, short.

Figure 2

O-GlcNAcylation pathway and its
association with glucose metabolism. (A) UDP-GlcNAc, the GlcNAc
donor molecule, is synthesized via the HBP, a metabolic branch
stemming from glycolysis. Glycolysis is associated with other
metabolic pathways, including the TCA cycle, OxPhos, PPP and
one-carbon cycle. (B) HBP pathway integrates glucose, amino acid,
lipid and nucleotide metabolism in the synthesis of the donor
molecule UDP-GlcNAc. Figure constructed using BioArt
(bioart.niaid.nih.gov/). UDP-GlcNAc, uridine diphosphate
N-acetylglucosamine; HBP, hexosamine biosynthesis pathway; TCA,
tricarboxylic acid cycle; OxPhos, oxidative phosphorylation; PPP,
pentose phosphate pathway; OGT, O-GlcNAc transferase; OGA,
O-GlcNAcase; PFK, phosphofructokinase; G6P, glucose-6-phosphate;
F1,6P, fructose 1,6-bisphosphate; G3P, glyceraldehyde-3-phosphate;
1,3PBG, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; PEP,
phosphoenolpyruvate; PGK, phosphoglycerate kinase; PK, pyruvate
kinase; LDHA, lactate dehydrogenase A; PDH, pyruvate dehydrogenase;
GFAT, glutamine fructose-6-phosphate amidotransferase; Fruc,
fructose; UAP, UDP-N-acetylglucosamine pyrophosphorylase 1; Glut,
glucose transporter; UTP, uridine triphosphate.

Figure 3

OGT mRNA expression status and
association with poor prognosis in certain GI tract cancers in
TCGA. (A) OGT mRNA expression relative to normal samples in various
cancer types. GI tract cancer and CCAs are highlighted in yellow
and red, respectively. Association between OGT mRNA expression and
prognosis of (B) ESCA, (C) COAD, (D) STAD, (E) HCC and (F) CCA. (G)
Association between OGT mRNA expression and tumor stage in CCA from
TCGA data analyzed with Gene Expression Profiling Interactive
analysis stage plot. OGT, O-GlcNAc transferase; TPM, transcripts
per million; RSEM, release sequence expression measurer; GI,
gastrointestinal; TCGA, The Cancer Genome Atlas; CCA,
cholangiocarcinoma; ESCA, esophageal carcinoma; COAD, colon
adenocarcinoma; STAD, stomach adenocarcinoma; HCC, hepatocellular
carcinoma.

Figure 4

Schematic representation of the role
of O-GlcNAcylation in CCA-relevant oncogenic pathways, including
cell proliferation, metastasis, metabolic reprogramming and
angiogenesis. Oncogenic regulators that exhibit a positive
feed-forward relationship with OGT and/or O-GlcNAcylation,
contributing to CCA progression and survival, are highlighted in
red. Figure constructed using BioRender (biorender.com/). CCA,
cholangiocarcinoma; OGT, O-GlcNAc transferase; MDM2, mouse double
minute 2 homolog; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate
dehydrogenase; OxPhos, oxidative phosphorylation; TCA,
tricarboxylic acid cycle; PGK, phosphoglycerate kinase; PPP,
pentose phosphate pathway; PKM2, pyruvate kinase M2; G6PD,
glucose-6-phosphate dehydrogenase; PFK, phosphofructokinase; AGER,
advanced glycosylation end product-specific receptor; UAP1,
UDP-N-acetylglucosamine pyrophosphorylase 1; HBP, hexosamine
biosynthesis pathway; IDH, isocitrate dehydrogenase; Glut, glucose
transporter; FASN, fatty acid synthase; SREBP-1, sterol regulatory
element-binding protein 1; ACSL4, acyl-CoA ligase 4; SRPK2,
serine/arginine-rich protein kinase 2; GFAT, glutamine
fructose-6-phosphate amidotransferase; RACK1, ribosomal receptor
for activated C-kinase 1.

Figure 5

Schematic of the role of
O-GlcNAcylation in cholangiocarcinoma-relevant programmed cell
death and tumor-associated inflammation pathways. Hh signaling
which exhibits a positive feed-forward association with OGT and/or
O-GlcNAcylation is shown in red. Figure constructed using BioRender
(biorender.com/). Hh, hedgehog; OGT, O-GlcNAc transferase; ATG,
autophagy-related protein; ULK1, Unc-51-like kinase 1; SNAP-29,
synaptosome associated protein 29; SLC7A11, solute carrier family 7
member 11; GSH, glutathione; ASNS, asparagine synthetase; GPT2,
glutamate pyruvate transaminase 2; CBS, cystathionine β-synthase;
FTH1, ferritin heavy chain 1; RIPK, receptor-interacting protein
kinase; MLKL, mixed lineage kinase domain like pseudokinase; YBX-1,
Y-box binding protein 1; CAF, cancer-associated fibroblast; GLI,
glioma-associated oncogene homolog.
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Copy and paste a formatted citation
Spandidos Publications style
Charoensuksai P and Jirawatnotai S: O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review). Oncol Rep 54: 119, 2025.
APA
Charoensuksai, P., & Jirawatnotai, S. (2025). O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review). Oncology Reports, 54, 119. https://doi.org/10.3892/or.2025.8952
MLA
Charoensuksai, P., Jirawatnotai, S."O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review)". Oncology Reports 54.4 (2025): 119.
Chicago
Charoensuksai, P., Jirawatnotai, S."O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review)". Oncology Reports 54, no. 4 (2025): 119. https://doi.org/10.3892/or.2025.8952
Copy and paste a formatted citation
x
Spandidos Publications style
Charoensuksai P and Jirawatnotai S: O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review). Oncol Rep 54: 119, 2025.
APA
Charoensuksai, P., & Jirawatnotai, S. (2025). O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review). Oncology Reports, 54, 119. https://doi.org/10.3892/or.2025.8952
MLA
Charoensuksai, P., Jirawatnotai, S."O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review)". Oncology Reports 54.4 (2025): 119.
Chicago
Charoensuksai, P., Jirawatnotai, S."O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review)". Oncology Reports 54, no. 4 (2025): 119. https://doi.org/10.3892/or.2025.8952
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