Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Shanghai Fifth People's Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, 131 Dongan Road, Shanghai 200032, China.
Brief Bioinform. 2024 Jul 25;25(5). doi: 10.1093/bib/bbae415.
Cancerous genetic mutations result in a complex and comprehensive post-translational modification (PTM) dynamics, in which protein succinylation is well known for its ability to reprogram cell metabolism and is involved in the malignant evolution. Little is known about the regulatory interactions between succinylation and other PTMs in the PTM network. Here, we developed a conjoint analysis and systematic clustering method to explore the intermodification communications between succinylome and phosphorylome from eight lung cancer patients. We found that the intermodification coorperation in both parallel and series. Besides directly participating in metabolism pathways, some phosphosites out of mitochondria were identified as an upstream regulatory modification directing succinylome dynamics in cancer metabolism reprogramming. Phosphorylated activation of histone deacetylase (HDAC) in lung cancer resulted in the removal of acetylation and favored the occurrence of succinylation modification of mitochondrial proteins. These results suggest a tandem regulation between succinylation and phosphorylation in the PTM network and provide HDAC-related targets for intervening mitochondrial succinylation and cancer metabolism reprogramming.
癌症基因突变导致复杂而全面的翻译后修饰（PTM）动态，其中蛋白质琥珀酰化因其能够重新编程细胞代谢并参与恶性演变而广为人知。关于 PTM 网络中琥珀酰化和其他 PTM 之间的调节相互作用知之甚少。在这里，我们开发了一种联合分析和系统聚类方法，从 8 名肺癌患者中探索琥珀酰组和磷酸组之间的互修饰通讯。我们发现，在平行和串联中都存在互修饰协同作用。除了直接参与代谢途径外，一些线粒体外的磷酸化位点被鉴定为上游调节修饰，可指导癌症代谢重编程中的琥珀酰组动力学。肺癌中组蛋白去乙酰化酶（HDAC）的磷酸化激活导致乙酰化的去除，并有利于线粒体蛋白的琥珀酰化修饰的发生。这些结果表明 PTM 网络中琥珀酰化和磷酸化之间存在串联调节，并为干预线粒体琥珀酰化和癌症代谢重编程提供了与 HDAC 相关的靶标。
