共因子分析揭示琥珀酰化组与磷酸化组之间的失衡HDAC磷酸化驱动的琥珀酰化动态变化在肺癌中的作用

Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer

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BRIEFINGS IN BIOINFORMATICS

影响因子:7.7

分区:生物学2区 / 数学与计算生物学1区生化研究方法2区

发表日期:2024 Jul 25

作者: Yifan Guo, Haoyu Wen, Zongwei Chen, Mengxia Jiao, Yuchen Zhang, Di Ge, Ronghua Liu, Jie Gu

DOI: 10.1093/bib/bbae415

摘要

癌症相关的遗传突变导致复杂且全面的翻译后修饰（PTM）动力学，其中蛋白质琥珀酰化以其重塑细胞代谢的能力而闻名，并参与恶性演化。关于琥珀酰化与PTM网络中其他修饰之间的调控相互作用尚不充分了解。在本研究中，我们开发了一种联合分析和系统聚类方法，探索来自八位肺癌患者的琥珀酰组与磷酸化组之间的相互修饰通信。我们发现两者之间的相互修饰协作既存在平行也存在串联。此外，除直接参与代谢途径外，还鉴定出线粒体外的某些磷酸位点作为上游调控修饰，指导癌症代谢重编程中的琥珀酰化动态。肺癌中组蛋白去乙酰酶（HDAC）磷酸化的激活导致乙酰化的去除，并促进线粒体蛋白的琥珀酰化修饰。这些结果提示在PTM网络中琥珀酰化与磷酸化之间存在串联调控关系，并为干预线粒体琥珀酰化和癌症代谢重编程提供了HDAC相关的潜在靶点。

Abstract

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.