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.

中文翻译：

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与源自患者的异种移植（PDX）小鼠模型中的正常肌肉相比，组蛋白H3K4me3和H3K9me3在软组织肉瘤中超甲基化：是癌症蛋氨酸成瘾的指标

蛋氨酸成瘾是我们在半个多世纪前发现的癌症的基本特征和普遍特征[美国国家科学院院刊73（1976）1523-1527]。蛋氨酸成瘾被定义为尽管具有从高半胱氨酸合成蛋氨酸的正常能力，但对于所有类型的癌细胞都需要外源性蛋氨酸。癌症的蛋氨酸成瘾被称为霍夫曼效应，类似于癌细胞对葡萄糖的高需求的沃伯格效应。蛋氨酸成瘾是由于过度的甲基化反应导致癌细胞中高的蛋氨酸通量，这导致它们由于游离的蛋氨酸和S-腺苷蛋氨酸的消耗而在蛋氨酸限制下选择性地被阻滞。最近，我们显示了蛋氨酸上瘾的癌细胞对甲基化组蛋白H3赖氨酸标记的甲基化程度过高，而正常细胞或从蛋氨酸上瘾的癌细胞衍生的低恶性蛋氨酸非依赖性回复子中甲基化水平并不高。在本报告中，我们显示在最常见的软组织肉瘤：黏膜原纤维肉瘤，未分化的多形性肉瘤（UPS）和脂肪肉瘤的患者源异种移植（PDX）小鼠模型中，组蛋白H3K4me3和H3K9me3与正常肌肉相比具有超甲基化组织。关于组蛋白H3过甲基化作为恶性肿瘤的潜在可能性，我们将与我们以前的报告一起讨论这一新结果。我们显示，在最常见的软组织肉瘤的患者源异种移植（PDX）小鼠模型中：粘膜纤维肉瘤，未分化的多形性肉瘤（UPS）和脂肪肉瘤，与正常肌肉组织相比，组蛋白H3K4me3和H3K9me3过度甲基化。关于组蛋白H3过度甲基化作为恶性肿瘤基础的潜力，我们将与我们以前的报告一起讨论这一新结果。我们显示，在最常见的软组织肉瘤的患者源异种移植（PDX）小鼠模型中：粘膜纤维肉瘤，未分化的多形性肉瘤（UPS）和脂肪肉瘤，与正常肌肉组织相比，组蛋白H3K4me3和H3K9me3过度甲基化。关于组蛋白H3过甲基化作为恶性肿瘤的潜在可能性，我们将与我们以前的报告一起讨论这一新结果。