IDDF2024-ABS-0443 Malonylation of CAP1 promotes lymph node metastasis in gastric cancer by boosting myosin depolymerization and RNA polymerase ii-mediated transcription elongation

Background

Lymph node metastasis (LNM) in gastric cancer (GC) stands as the pivotal determinant of patient prognosis. This phenomenon is a multifaceted process entwined with numerous factors and genes. Notably, post-translational modifications wield a significant influence in orchestrating tumor onset and advancement by reshaping protein structure and function. Malonylation modification, a recently unveiled post-translational alteration employing malonyl-CoA as its substrate, has emerged as a critical player. This study endeavors to delve into the functions and underlying mechanisms of malonylation-modified proteins in the context of LNM in GC.

Methods

This study utilizes a dual analysis of protein modification proteomics and proteomics to unveil that individuals with LNM in GC showcase elevated levels of malonylation modification. Specifically, malonylated proteins play a pivotal role in modulating the assembly and disassembly of the cellular cytoskeleton. By employing diverse methodologies such as bioinformatics, cytology, molecular biology, and high-throughput sequencing, this research elucidates the impact of malonylation modification on the regulation of LNM in GC through Adenylate Cyclase-Associated Protein 1 (CAP1), a significant myosin depolymerization factor.

Results

CAP1 is highly expressed in gastric cancer tissues and cells, correlating closely with poor prognosis in patients. Malonylation modification of lysine residues in CAP1 is notably elevated in gastric cancer patients with LNM. Our findings reveal that CAP1 plays a critical role in regulating the formation of invasive pseudopods in cells, facilitating the tubulization and migration of lymphatic endothelial cells, with malonylation modification playing a key role in sustaining this function. Mechanistically, malonylation modification enhances the interaction of CAP1 with myosin regulatory factors and transcription elongation factors, thereby amplifying CAP1's regulation of RNA polymerase (Pol) II-Ser2 phosphorylation and transcription elongation. The extent of malonylation is predominantly governed by malonyl-CoA carboxylase ACC1 and deacetylase SIRT5, and attenuating tumor metastasis driven by malonylation modification can be achieved by modulating their substrates or enhancing SIRT5 expression.

Conclusions

This study reveals the significant role of CAP1 malonylation modification in the LNM of GC, proposing new mechanisms and insights into tumor metastasis from the perspectives of tumor metabolism and cytoskeleton regulation.