Systematic Proteome and Lysine Succinylome Analysis Reveals Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and posttranslational modifications (PTMs) leading to the pathogenesis of ESCC remain unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome, and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and PTM pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo. This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology. [Display omitted] •Quantitative proteomes, lysine acetylome, and succinylome of SHEEC and SHEE cells.•Lysine succinylation is significantly downregulated in SHEEC cells.•ESCC malignant behaviors are inhibited once the level of succinylation is restored.•Hyposuccinylation is confirmed in primary ESCC specimens. The proteome, phosphorylome, lysine acetylome, and succinylome were quantified for esophageal squamous cell carcinoma (ESCC) and matched control cells. Our results identify hyposuccinylation in cancer cells and reveal that ESCC malignant behaviors are inhibited once the level of succinylation was restored in vitro or in vivo, which is further confirmed in primary ESCC specimens. Our findings demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing a new insight into the functional significance of posttranslational modification in cancer biology.