CHD4 drives gastric cancer metastasis via MYH9/GSK3β/β-catenin axis and WNT/EMT pathway activation.

Gastric cancer (GC) metastasis remains a significant cause of cancer-related mortality, yet the molecular mechanisms underlying this process have not been fully elucidated. CHD4, a chromatin remodeling factor, has been associated with oncogenic processes, but its precise role in GC metastasis has not been defined. In this study, we identify CHD4 as a critical regulator of GC metastasis through the MYH9/GSK3β/β-catenin axis and the activation of the WNT pathway and epithelial-mesenchymal transition (EMT). Clinically, CHD4 was significantly overexpressed in GC tissues and strongly correlated with advanced disease stages and poor prognosis. Mechanistically, CHD4 interacted with MYH9 via its ATPase domain and promoted the nuclear-to-cytoplasmic translocation of MYH9, thereby enabling MYH9 to orchestrate inhibitory phosphorylation and ubiquitination-dependent degradation of GSK3β. This, in turn, stabilized β-catenin, leading to its nuclear accumulation and activation of downstream WNT target genes, such as Cyclin D1, along with the induction of EMT. Functionally, suppression of CHD4 expression inhibited GC cell migration, invasion, and metastasis in vivo, while MYH9 restoration reversed these effects. Collectively, these findings establish CHD4 as a key regulator of GC metastasis through the MYH9/GSK3β/β-catenin axis and underscore its potential as a therapeutic target for inhibiting GC progression.