# SMARCD3 Promotes Epithelial–Mesenchymal Transition in Gastric Cancer by Integrating PI3K-AKT and WNT/β-Catenin Pathways

## TL;DR

This study shows that SMARCD3 promotes aggressive behavior in gastric cancer by activating key signaling pathways linked to cancer spread.

## Contribution

The study reveals a novel role of SMARCD3 in integrating PI3K-AKT and WNT/β-catenin pathways to drive EMT in gastric cancer.

## Key findings

- SMARCD3 overexpression correlates with poor survival and promotes EMT in gastric cancer.
- SMARCD3 activates PI3K-AKT and WNT/β-catenin pathways, increasing Snail/Slug expression and cell invasion.
- Inhibiting PI3K or blocking WNT signaling reduces SMARCD3-driven EMT effects.

## Abstract

This study demonstrates that SMARCD3 overexpression in gastric cancer (GC) serves as a negative prognostic biomarker, correlating with significantly poorer overall survival. Mechanistically, high SMARCD3 expression drives tumor aggressiveness by promoting the Epithelial–Mesenchymal Transition (EMT) phenotype. This promotion involves the upregulation of cellular migration and invasion, which is linked to the activation and crosstalk of key oncogenic pathways, specifically the PI3K-AKT (p-AKT-S473, PI3Kp85) and WNT/β-catenin axes. These results identify SMARCD3 as a critical potential therapeutic target for EMT-driven GC progression.

Background: Epithelial–mesenchymal transition (EMT) is a fundamental process that drives invasion and metastasis in patients with diffuse-type gastric cancer (DGC). The role of SMARCD3, a subunit of the SWI/SNF chromatin remodeling complex, in this process is largely unknown. The aim of this study is to elucidate the molecular mechanism through which SMARCD3 integrates with the PI3K-AKT and WNT/β-catenin signaling pathways to promote EMT and gastric cancer progression. Methods: Stable SMARCD3-overexpressing MKN45 and MKN74 cell lines were established. RNA sequencing (RNA-seq) was performed to investigate signaling alterations. Western blot analysis confirmed the expression of EMT markers (Snail and Slug) and the phosphorylation of AKT (Ser473) and GSK3β (Ser9). PI3K dependency was tested using the inhibitor LY294002. Cooperative effects were examined by activating the WNT pathway with WNT3A. Results: SMARCD3 overexpression upregulated PI3K-AKT and WNT signaling, which correlated with increased Snail/Slug expression and increased AKT/GSK3β phosphorylation. GSK3β inactivation (pSer9) stabilizes Snail, driving EMT. LY294002 treatment suppressed Snail/Slug expression, attenuated AKT activation, and reversed the mesenchymal phenotype. Furthermore, WNT3A treatment synergistically increased nuclear Snail accumulation. Conclusions: SMARCD3 acts as a critical epigenetic regulator that promotes EMT in patients with gastric cancer through the integration of the PI3K-AKT and WNT/β-catenin pathways. Targeting this SMARCD3-mediated mechanism offers a promising therapeutic strategy to inhibit metastasis and improve outcomes for patients with gastric cancer.