KDM1A-driven RNF81 downregulation promotes gastric cancer progression via KLF4 destabilization.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, especially in East Asia, with a low 5-year survival rate due to late-stage diagnosis. Identifying molecular mechanisms that regulate GC progression is critical for improving clinical outcomes. RNF81, a member of the tripartite motif (TRIM) family, has demonstrated diverse roles in various cancers. In this study, we uncover its tumor-suppressive function in GC through novel regulatory pathways. Analysis of clinical data and tissue microarrays revealed that RNF81 expression is significantly downregulated in GC tissues and positively correlates with patient survival. Mechanistically, we identified lysine demethylase KDM1A as a key repressor of RNF81 expression. KDM1A recruits transcription factor E2F1 to form a transcriptional repressor complex, reducing H3K4me1 and H3K4me2 levels at the RNF81 promoter. Functional studies showed that RNF81 stabilizes the tumor suppressor KLF4 by binding through its SPRY domain, thereby inhibiting KLF4 ubiquitination and degradation. Overexpression of RNF81 suppressed GC cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo, effects that were partially rescued by KLF4 knockdown. These findings reveal a novel KDM1A-RNF81-KLF4 regulatory axis in GC and highlight RNF81 as a potential therapeutic target for GC treatment. Targeting this pathway may offer promising strategies to improve outcomes for GC patients.