Knockdown of <i>SIN3A</i> Derepresses <i>SYNPO2</i> Transcription and Inhibits Gastric Cancer Cell Progression

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 (<i>SIN3A</i>) and synaptopodin-2 (<i>SYNPO2</i>) may influence GC progression, this study aimed to investigate the impact of <i>SIN3A</i>-mediated regulation of <i>SYNPO2</i> on GC progression. Methods: The expression levels of <i>SYNPO2</i> and its binding interaction with <i>SIN3A</i> in GC were analyzed using bioinformatics tools. The binding sites between <i>SIN3A</i> and <i>SYNPO2</i> were validated through a dual-luciferase reporter assay. Furthermore, the biological function of <i>SIN3A</i> in regulating <i>SYNPO2</i> 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 <i>SYNPO2</i> expression (<i>p</i> < 0.01). <i>SYNPO2</i> overexpression inhibited GC cell viability, colony formation, migration, and invasion, while promoting apoptosis (<i>p</i> < 0.01). <i>SYNPO2</i> was found to bind to <i>SIN3A</i> and mediate its transcriptional repression. <i>SIN3A</i> 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 <i>SIN3A</i> knockdown produced the opposite effects (<i>p</i> < 0.05). The effects of <i>SIN3A</i> knockdown were reversed by <i>SYNPO2</i> silencing in GC cells (<i>p</i> < 0.05). Conclusion: <i>SIN3A</i> knockdown-mediated upregulation of <i>SYNPO2</i> suppresses GC malignancy processes, offering insights into a novel strategy for developing targeted therapies for gastric cancer.