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DNA methyltransferase 3a-induced hypermethylation of the fructose-1,6-bisphosphatase-2 promoter contributes to gastric carcinogenesis

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Abstract

Background

Aberrant DNA methylation has been implicated in the development of gastric cancer (GC). In our previous study, we demonstrated that fructose-1,6-bisphosphatase-2 (FBP2), an enzyme that suppresses cell glycolysis and growth, is downregulated in GC due to promoter methylation. However, the precise mechanism underlying this process remains unknown. Thus, this study aimed to elucidate the mechanisms involved in FBP2 promoter hypermethylation.

Methods and results

The methylation levels in GC and normal adjacent tissues were quantified using methylation-specific polymerase chain reaction. FBP2 promoter was frequently hypermethylated in primary GC tissues compared to adjacent normal tissues. To explore the functional consequences of this hypermethylation, we employed small interfering RNA-mediated knockdown of DNA methyltransferase 3a (DNMT3a) in GC cells. FBP2 expression increased following DNMT3a knockdown, suggesting that reduced methylation of the FBP2 promoter contributed to this upregulation. To further investigate this interaction, chromatin immunoprecipitation assays were conducted. The results confirmed an interaction between DNMT3a and the FBP2 promoter region, providing evidence that DNMT3a-mediated hypermethylation of the FBP2 promoter promotes GC progression.

Conclusions

This study provides evidence that DNMT3a is involved in the hypermethylation of the FBP2 promoter and regulation of GC cell metabolism. Hypermethylation of the FBP2 promoter may be a promising prognostic biomarker in GC.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

DMEM:

Dulbecco’s Modified Eagle

DNMTs:

DNA methyltransferases

FBP:

Fructose-1,6-bisphosphatase

GC:

Gastric cancer

HRP:

Horseradish peroxidase

MSP:

Methylation-specific polymerase chain reaction products

PVDF:

Polyvinylidene fluoride

RIPA:

Radioimmunoprecipitation assay

SD:

Standard deviation

siRNA:

Small interfering ribonucleic acid

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Funding

This project received support from the National Natural Science Foundation of China (Grant Number 81802807).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200001, China

    Yu Huang & Hong Lu

  2. Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China

    He Li

Authors
  1. Yu Huang
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  2. Hong Lu
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  3. He Li
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Contributions

YH collected data and drafted the manuscript. YH and HL contributed to cell experiment, statistical analysis and interpretation of all the data. HL and HL designed the study and reviewed the manuscript. All authors have read and approved the final manuscript for publication.

Corresponding authors

Correspondence to Hong Lu or He Li.

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None.

Ethical approval

This study was conducted with the approval of the Institutional Ethical Standards Committee of Renji Hospital (No. 2017-114-CR-02).

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All participants provided written informed consent before their inclusion in the study.

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Huang, Y., Lu, H. & Li, H. DNA methyltransferase 3a-induced hypermethylation of the fructose-1,6-bisphosphatase-2 promoter contributes to gastric carcinogenesis. Mol Biol Rep 51, 78 (2024). https://doi.org/10.1007/s11033-023-08966-5

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