Regulators of Cancer Progression: Succinylation

Abstract

Lysine succinylation is a recently discovered post-translational protein modification, the process of which requires the participation of various enzymes. The close association between cancer and protein post-translational modifications (PTMs), such as acetylation and phosphorylation, has been extensively investigated and well-established. In recent years, growing attention has been directed toward the role of succinylation in cancer progression. Accumulating evidence demonstrates that protein succinylation and desuccinylation play critical roles in promoting the development of various cancers, including lung, prostate, and renal cancers. Notably, the primary substrates undergoing succinylation are non-histone proteins. Therefore, elucidating the functions of cancer-related succinylated proteins is essential for identifying novel therapeutic targets. This review comprehensively summarizes current research advances regarding protein succinylation in common cancers and discusses the progress in developing succinylation-targeting drugs. Specifically, we focus on the molecular mechanisms by which succinylation regulates cancer progression, along with the identification of key succinylation sites. Our discussion aims to provide valuable insights for future research and the development of innovative cancer treatments.

Keywords: cancer; drug; succinylation; tumor.

Figure 1

Lysine succinylation process. The figure illustrates the process of lysine undergoing succinylation modification in the presence of succinyl-CoA, succinyl transferase, and desuccinylase. Conversion of alpha-ketoglutarate from oxaloacetic acid leads to the formation of succinyl-CoA via α-KDGHC. Valine, isoleucine, and heme lead to methylmalonyl CoA, which is then catalyzed by the MCM to produce succinyl-CoA. The charge of the lysine side chain changes before and after the reaction, transforming from a positively charged −NH₃⁺ to a negatively charged −COO⁻.

Figure 2

The mechanism of action of succinylation in cancer. The figure shows the succinylation modification in nine common types of cancer. Both black dotted lines and gradient lines represent promotion, and red dotted lines represent inhibition. (A). Lung adenocarcinoma: SUCLA2 and SUCLG2 influence the succinylation of related proteins through their concentrations, thereby promoting cell migration and proliferation; PGK1 and P23 self-succinylation, respectively, promote tumor metabolic reprogramming and tumor growth. (B). Prostate cancer: The succinylation of SP5, CTBP1, and LDHA proteins affects transcription and glycolysis. (C). Renal cell carcinoma: The succinylation of LRPPRC and EIF3B proteins affects RNA modification, while PDHA1 succinylation promotes metabolic reprogramming. (D). Thyroid cancer: Desamidation of LDHA and KIF23 promotes metabolic reprogramming and cell migration. (E). Breast cancer: Desamidation of IDH2 promotes cell proliferation. (F). Hepatocellular carcinoma: Self-succinylation of PGAM1, LACTB, and OXCT1 promotes cell proliferation; desuccinylation of ACOX2 aids in BC generation; succinylation of H3 promotes tumorigenesis; desuccinylation of PRMT5 increases cell migration. (G). Ovarian cancer: Succinylation of MFF promotes mitochondrial fission and maintenance of stem cell pluripotency. (H). Gastric cancer: PKM2 succinylation promotes EMP, while LDHA and FBN1 succinylation inhibit self-degradation. (I). Colorectal cancer: Both CS and ME2 desuccinylation promote cell proliferation via the TCA cycle. Figure created using BioRender.com (accessed on 13 August 2025).

Figure 3

The function of succinylation in glioma and lymphoma. The figure shows succinylation occurring in glioma and nasal-type extranodal natural killer/T-cell lymphoma. Figure created using BioRender.com (accessed on 9 August 2025).