Succinylation: A Functional Nexus Between Metabolic Reprogramming and Epigenetic Modifications in Cancer.

Metabolic reprogramming and epigenetic remodeling are critical features of tumorigenesis. The process of metabolic reprogramming causes metabolites like Succinyl-CoA to accumulate. Succinylation, which depends on succinyl-CoA as the direct donor group, plays a crucial role in regulating cancer metabolism. This involves the transfer of the succinyl group to the lysine residues of substrate proteins resulting in the alteration of the conformation and function of the proteins, modulating several signaling pathways, many of them involved in metabolism. There is growing evidence that succinylation can alter the activity and stability of metabolic enzymes and reshape metabolic networks. Furthermore, it precisely regulates gene expression through the epigenetic modification mechanisms of the histones and non-histone proteins. Lysine succinylation is thus a crucial hub linking tumor metabolic reprogramming and epigenetic remodeling. This review systematically summarizes the dynamic regulatory mechanisms of lysine succinylation and its critical roles in tumor metabolic reprogramming and epigenetic regulation. In the end, we discuss the crosstalk between succinylation and other post-translational modifications (PTMs) as well as recent advances in cancer therapies targeting succinylation.