Methionine addiction is a fundamental and general hallmark of
cancer cells, which require exogenous
methionine, despite their ability to synthesize normal amounts of
methionine from
homocysteine. In contrast,
methionine-independent normal cells do not require exogenous
methionine in the presence of a
methionine precursor. The
methionine addiction of
cancer cells is due to excess transmethylation reactions. We have previously shown that
histone H3 lysine marks are over-methylated in
cancer cells and the over-methylation is unstable when the
cancer cells are restricted of
methionine. In the present study, we show that
methionine-addicted
osteosarcoma cells are sensitive to both
methotrexate (MTX) and recombinant
methioninase (rMETase), but they affect
histone H3 lysine-methylation in the opposite direction. Concentrations of MTX and rMETase, which inhibit
osteosarcoma cells viability to 20%, had opposing effects on the status of
histone methylation of H3K9me3 and H3K27me3. rMETase significantly decreased the amount of H3K9me3 and H3K27me3. In contrast, MTX significantly increased the amount of H3K9me and H3K27me3. The results suggest that increase or decrease in these methylated
histone lysine marks is associated with proliferation arrest of
methionine-addicted
osteosarcoma.