Wnt/β-catenin signaling regulates amino acid metabolism through the suppression of CEBPA and FOXA1 in liver cancer cells.
Humans
Hepatocyte Nuclear Factor 3-alpha
/ metabolism
Wnt Signaling Pathway
Liver Neoplasms
/ metabolism
CCAAT-Enhancer-Binding Proteins
/ metabolism
beta Catenin
/ metabolism
Gene Expression Regulation, Neoplastic
Amino Acids
/ metabolism
Cell Line, Tumor
Transcription Factor 7-Like 2 Protein
/ metabolism
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
29 Apr 2024
29 Apr 2024
Historique:
received:
04
11
2023
accepted:
16
04
2024
medline:
30
4
2024
pubmed:
30
4
2024
entrez:
29
4
2024
Statut:
epublish
Résumé
Deregulation of the Wnt/β-catenin pathway is associated with the development of human cancer including colorectal and liver cancer. Although we previously showed that histidine ammonia lyase (HAL) was transcriptionally reduced by the β-catenin/TCF complex in liver cancer cells, the mechanism(s) of its down-regulation by the complex remain to be clarified. In this study, we search for the transcription factor(s) regulating HAL, and identify CEBPA and FOXA1, two factors whose expression is suppressed by the knockdown of β-catenin or TCF7L2. In addition, RNA-seq analysis coupled with genome-wide mapping of CEBPA- and FOXA1-binding regions reveals that these two factors also increase the expression of arginase 1 (ARG1) that catalyzes the hydrolysis of arginine. Metabolome analysis discloses that activated Wnt signaling augments intracellular concentrations of histidine and arginine, and that the signal also increases the level of lactic acid suggesting the induction of the Warburg effect in liver cancer cells. Further analysis reveals that the levels of metabolites of the urea cycle and genes coding its related enzymes are also modulated by the Wnt signaling. These findings shed light on the altered cellular metabolism in the liver by the Wnt/β-catenin pathway through the suppression of liver-enriched transcription factors including CEBPA and FOXA1.
Identifiants
pubmed: 38684876
doi: 10.1038/s42003-024-06202-9
pii: 10.1038/s42003-024-06202-9
doi:
Substances chimiques
Hepatocyte Nuclear Factor 3-alpha
0
FOXA1 protein, human
0
CEBPA protein, human
0
CCAAT-Enhancer-Binding Proteins
0
beta Catenin
0
Amino Acids
0
Transcription Factor 7-Like 2 Protein
0
CTNNB1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
510Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP20K07563
Informations de copyright
© 2024. The Author(s).
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