Giallongo Sebastiano, Costa Francesco, Longhitano Lucia, Giallongo Cesarina, Ferrigno Jessica, Tropea Emanuela, Vicario Nunzio, Li Volti Giovanni, Parenti Rosalba, Barbagallo Ignazio, Bramanti Vincenzo, Tibullo Daniele
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
Department of Medical-Surgical Science and Advanced Technologies "Ingrassia", University of Catania, 95123 Catania, Italy.
Metabolites. 2023 Jul 24;13(7):880. doi: 10.3390/metabo13070880.
Tumor onset and its progression are strictly linked to its metabolic rewiring on the basis of the Warburg effect. In this context, fumarate emerged as a putative oncometabolite mediating cancer progression. Fumarate accumulation is usually driven by fumarate hydratase (FH) loss of function, the enzyme responsible for the reversible conversion of fumarate into malate. Fumarate accumulation acts as a double edge sword: on one hand it takes part in the metabolic rewiring of cancer cells, while on the other it also plays a crucial role in chromatin architecture reorganization. The latter is achieved by competing with a-ketoglutarate-dependent enzymes, eventually altering the cellular methylome profile, which in turn leads to its transcriptome modeling. Furthermore, in recent years, it has emerged that FH has an ability to recruit DNA double strand breaks. The accumulation of fumarate into damaged sites might also determine the DNA repair pathway in charge for the seizure of the lesion, eventually affecting the mutational state of the cells. In this work, we aimed to review the current knowledge on the role of fumarate as an oncometabolite orchestrating the cellular epigenetic landscape and DNA repair machinery.
肿瘤的发生及其进展与基于瓦伯格效应的代谢重编程密切相关。在此背景下，富马酸酯作为一种介导癌症进展的假定肿瘤代谢物而出现。富马酸酯的积累通常由富马酸水合酶（FH）功能丧失驱动，该酶负责富马酸酯与苹果酸之间的可逆转化。富马酸酯的积累犹如一把双刃剑：一方面它参与癌细胞的代谢重编程，另一方面它在染色质结构重组中也起着关键作用。后者是通过与依赖α-酮戊二酸的酶竞争来实现的，最终改变细胞的甲基化组图谱，进而导致其转录组重塑。此外，近年来发现FH具有招募DNA双链断裂的能力。富马酸酯在受损位点的积累也可能决定负责捕获损伤的DNA修复途径，最终影响细胞的突变状态。在这项工作中，我们旨在综述当前关于富马酸酯作为一种肿瘤代谢物在协调细胞表观遗传格局和DNA修复机制方面作用的知识。
