Aoki Yusuke, Tome Yasunori, Han Qinghong, Yamamoto Jun, Hamada Kazuyuki, Masaki Noriyuki, Bouvet Michael, Nishida Kotaro, Hoffman Robert M
AntiCancer Inc, 7917 Ostrow St, San Diego, CA, 92111, USA.
Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA, 92037-7220, USA.
Biochem Biophys Rep. 2021 Nov 26;28:101177. doi: 10.1016/j.bbrep.2021.101177. eCollection 2021 Dec.
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.
甲硫氨酸成瘾是癌细胞的一个基本且普遍的特征，尽管癌细胞有能力从同型半胱氨酸合成正常量的甲硫氨酸，但它们仍需要外源性甲硫氨酸。相比之下，不依赖甲硫氨酸的正常细胞在有甲硫氨酸前体存在时不需要外源性甲硫氨酸。癌细胞的甲硫氨酸成瘾是由于过量的转甲基反应。我们之前已经表明，癌细胞中组蛋白H3赖氨酸标记过度甲基化，并且当癌细胞的甲硫氨酸受到限制时，这种过度甲基化是不稳定的。在本研究中，我们表明对甲硫氨酸成瘾的骨肉瘤细胞对甲氨蝶呤（MTX）和重组甲硫氨酸酶（rMETase）均敏感，但它们对组蛋白H3赖氨酸甲基化的影响方向相反。抑制骨肉瘤细胞活力至20%的MTX和rMETase浓度，对H3K9me3和H3K27me3组蛋白甲基化状态有相反的影响。rMETase显著降低了H3K9me3和H3K27me3的量。相比之下，MTX显著增加了H3K9me和H3K27me3的量。结果表明，这些甲基化组蛋白赖氨酸标记的增加或减少与对甲硫氨酸成瘾的骨肉瘤的增殖停滞有关。
