Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells

Biochem Biophys Res Commun. 2020 Dec 17;533(4):1034-1038. doi: 10.1016/j.bbrc.2020.09.108. Epub 2020 Oct 3.


Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction prevents cancer cells, but not normal cells from proliferation under methionine restriction (MR). Previous studies reported that MR altered the histone methylation levels in methionine-addicted cancer cells. However, no study has yet compared the status of histone methylation status, under MR, between cancer cells and normal cells. In the present study, we compared the histone methylation status between cancer cells and normal fibroblasts of H3K4me3 and H3K9me3, using recombinant methioninase (rMETase) to effect MR. Human lung and colon cancer cell lines and human normal foreskin fibroblasts were cultured in control medium or medium with rMETase. The viability of foreskin fibroblasts was approximately 10 times more resistant to rMETase than the cancer cells in vitro. Proliferation only of the cancer cells ceased under MR. The histone methylation status of H3K4me3 and H3K9me3 under MR was evaluated by immunoblotting. The levels of the H3K4me3 and H3K9me3 were strongly decreased by MR in the cancer cells. In contrast, the levels of H3K4me3 and H3K9me3 were not altered by MR in normal fibroblasts. The present results suggest that histone methylation status of H3K4me3 and H3K9me3 under MR was unstable in cancer cells but stable in normal cells and the instability of histone methylation status under MR may determine the high methionine dependency of cancer cells to survive and proliferate.

Keywords: Histone methylation; Methioninase; Methionine addiction; Methionine dependence; Methionine restriction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-Sulfur Lyases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cell Survival / physiology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / metabolism*
  • Fibroblasts / metabolism*
  • Histones / metabolism*
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / metabolism*
  • Methionine / deficiency*
  • Methionine / metabolism*
  • Methylation
  • Recombinant Proteins


  • Histones
  • Recombinant Proteins
  • histone H3 trimethyl Lys4
  • Methionine
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase