AMPK Deficiency Increases DNA Methylation and Aggravates Colorectal Tumorigenesis in AOM/DSS Mice.
Genes (Basel)
; 15(7)2024 Jun 25.
Article
in En
| MEDLINE
| ID: mdl-39062614
ABSTRACT
The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azoxymethane
/
Colorectal Neoplasms
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DNA Methylation
/
Dioxygenases
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AMP-Activated Protein Kinases
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Carcinogenesis
Limits:
Animals
/
Humans
Language:
En
Journal:
Genes (Basel)
Year:
2024
Document type:
Article
Affiliation country:
United States