Background: The development of novel targeted therapies for gastric cancer (GC) has been significantly hindered by our limited understanding of the molecular mechanisms underlying its progression. As SIN3 transcription regulator family member A (SIN3A) and synaptopodin-2 (SYNPO2) may influence GC progression, this study aimed to investigate the impact of SIN3A-mediated regulation of SYNPO2 on GC progression.

Methods: The expression levels of SYNPO2 and its binding interaction with SIN3A in GC were analyzed using bioinformatics tools. The binding sites between SIN3A and SYNPO2 were validated through a dual-luciferase reporter assay. Furthermore, the biological function of SIN3A in regulating SYNPO2 was investigated in GC cells using gene silencing and overexpression approaches. Cell proliferation, colony formation, apoptosis, migration, and invasion were assessed using cell counting, colony formation assay, flow cytometry, wound healing, Transwell, and molecular analyses.

Results: GC cells presented significantly reduced SYNPO2 expression (p < 0.01). SYNPO2 overexpression inhibited GC cell viability, colony formation, migration, and invasion, while promoting apoptosis (p < 0.01). SYNPO2 was found to bind to SIN3A and mediate its transcriptional repression. SIN3A overexpression enhanced GC cell viability, colony formation, migration, and invasion, inhibited apoptosis, upregulated B-cell lymphoma 2 (Bcl-2), and downregulated Bcl-2-associated X protein (Bax) and cleaved caspase-3 expression, whereas SIN3A knockdown produced the opposite effects (p < 0.05). The effects of SIN3A knockdown were reversed by SYNPO2 silencing in GC cells (p < 0.05).

Conclusion: SIN3A knockdown-mediated upregulation of SYNPO2 suppresses GC malignancy processes, offering insights into a novel strategy for developing targeted therapies for gastric cancer.