Institute of Bioengineering, Research Center of Biotechnology RAS, Moscow, Russia.
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Epigenetics. 2022 Aug;17(8):894-905. doi: 10.1080/15592294.2021.1971372. Epub 2021 Sep 8.
Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene () by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type . We showed that global genome hypermethylation in mutants can be explained by transcriptional changes in and genes that cause the accumulation of 2-hydroxyglutarate - a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.
肿瘤抑制因子的高甲基化和肿瘤中其他 DNA 甲基化的异常改变在癌症进展中起重要作用。DNA 甲基化可受到各种环境条件的影响，包括缺氧。对缺氧的反应主要通过与 HIF1A 转录因子相关的转录程序的激活来实现。von Hippel-Lindau 肿瘤抑制基因 () 的失活（通过遗传或表观遗传事件），也会导致 HIF1A 的异常激活，是肾癌最常见的驱动事件。通过全基因组亚硫酸氢盐测序和 LC-MS，我们证明在常氧条件下， 失活会诱导人肾癌细胞的全基因组超甲基化。外源性表达野生型 可逆转这种效应。我们表明， 突变体中的全基因组超甲基化可以通过 和 基因的转录变化来解释，这些基因导致 2-羟戊二酸的积累 - 一种抑制 TET 酶 DNA 去甲基化的代谢物。与癌症中已知的 DNA 高甲基化情况不同，细胞中积累了野生型异柠檬酸脱氢酶的 2-羟戊二酸。
