Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.

中文翻译：

---

癌症和肿瘤起始细胞蛋氨酸依赖性的遗传，表观遗传和基因组机制：我们可以从叶酸和蛋氨酸循环中学到什么。

蛋氨酸依赖性是癌细胞的一个共同特征，如果没有外源蛋氨酸的恒定输入，即使存在前体高半胱氨酸也不能增殖。蛋氨酸合成酶催化蛋氨酸的内源性合成，蛋氨酸合成酶在维生素B12（钴胺素，cbl）存在下将5-甲基四氢叶酸（5-甲基THF）的甲基转移至高半胱氨酸。各种各样的机制可以产生它，包括体细胞突变，异常的DNA甲基化（突变）和基因表达的改变。据报道，约有二十种体细胞突变是蛋氨酸依赖性的原因。它们中的一些是贡献者，但仅靠它们自身不足以引起蛋氨酸依赖性。MMACHC基因表达的表观遗传失效触发了MeWo-LC1黑色素瘤癌细胞系蛋氨酸的依赖性。这种突变是由邻近基因PRDX1的反义反转录产生的。蛋氨酸依赖性涉及癌症干细胞中1-CM基因的异常表达。这与对蛋氨酸和SAM的需求增加有关，这不能被肺癌肿瘤领域甘氨酸脱羧酶途径的甲酸盐产量增加所抵消。胶质母细胞瘤U251的肿瘤球通过叶酸代谢的破坏而依赖于蛋氨酸。通过叶酸挽救胶质母细胞瘤干细胞的生长，显示出评估补充剂和饮食中叶酸对肿瘤发展风险的影响的重要性，尤其是在进行了叶酸强化食品强化的国家中。