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Metformin Reduces Histone H3K4me3 at the Promoter Regions of Positive Cell Cycle Regulatory Genes in Lung Cancer

Dongho Kim1, Yujin Kim1, Bo Bin Lee1

  • 1Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.

Cancers
|February 13, 2021
PubMed

Insights

Metformin reduces histone H3 lysine 4 trimethylation (H3K4me3) in lung cancer by downregulating MLL2, a key enzyme. This finding suggests MLL2 as a potential therapeutic target for lung adenocarcinoma.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Lung cancer is a leading cause of cancer-related mortality.
  • Epigenetic modifications, including histone methylation, play a crucial role in cancer development.
  • Metformin, a common diabetes drug, has shown potential anti-cancer properties.

Purpose of the Study:

  • To investigate the effects of metformin on epigenetic modifications in lung cancer cells.
  • To determine the role of histone H3 lysine 4 trimethylation (H3K4me3) and its associated enzymes in metformin's anti-cancer activity.
  • To explore MLL2 as a potential therapeutic target in non-small cell lung cancer (NSCLC).

Main Methods:

  • Treatment of lung cancer cells with metformin.
  • Analysis of H3K4me3 levels using quantitative assays.
  • Assessment of gene and protein expression of H3K4 methyltransferases (MLL1, MLL2, WDR82).
  • siRNA-mediated knockdown of MLL2 to evaluate its functional role.
  • Correlation analysis of MLL2 expression with patient survival data in NSCLC.

Main Results:

  • Metformin significantly reduced H3K4me3 levels at promoters of cell cycle genes, including CCNB2, CDK1, CDK6, and E2F8.
  • Metformin suppressed the expression of H3K4 methyltransferases MLL1, MLL2, and WDR82.
  • MLL2 knockdown decreased global H3K4me3 and inhibited lung cancer cell proliferation.
  • MLL2 overexpression was observed in 33% of NSCLC patients and correlated with poorer recurrence-free survival.
  • Metformin had minimal impact on DNA methylation and chromatin accessibility.

Conclusions:

  • Metformin reduces H3K4me3 levels in lung cancer cells, primarily through the downregulation of MLL2.
  • MLL2 plays a significant role in lung cancer cell proliferation and patient prognosis.
  • MLL2 represents a promising therapeutic target for improving outcomes in lung adenocarcinoma.
Keywords:
H3K4 methylationMLL2cell cyclelung cancermetformin

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