Histone H3K4me3 and H3K9me3 are super over-methylated in soft tissue sarcoma compared to normal muscle in patient-derived xenograft (PDX) mouse models: an indicator of cancer methionine addiction

Methionine addiction is a fundamental and general hallmark of cancer discovered by us almost a half-century ago [Proc Natl Acad Sci U S A 73 (1976) 1523-1527]. Methionine addiction is defined as the requirement, specific for cancer cells of all types, for exogenous methionine despite the normal ability to synthesize methionine from homocysteine. The methionine addiction of cancer is termed the Hoffman-effect, analogous to the Warburg-effect of the high glucose requirement of cancer cells. Methionine addiction is due to excess transmethylation reactions resulting in high methionine flux in cancer cells, which causes them to selectively arrest under methionine restriction due to depletion of free methionine and S-adenosyl methionine. Recently we have shown methionine-addicted cancer cells over-methylate histone H3 lysine marks which are not over-methylated in normal cells or in low-malignancy methionine-independent revertants derived from methionine-addicted cancer cells. In the present report, we show that in patient-derived xenograft (PDX) mouse models of the most common soft tissue sarcomas: myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS) and liposarcoma, histone H3K4me3 and H3K9me3 are super over-methylated compared to normal muscle tissue. This new result is discussed along with our previous reports, regarding the potential of histone H3 over-methylation as a basis of malignancy.