The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination.

Abstract

Ferroptosis is a novel form of cell death that is closely associated with the formation of many tumors. Our study focused on the mechanism by which long noncoding RNAs (lncRNAs) regulate ferroptosis in gastric cancer (GC) peritoneal metastasis (PM). We utilized lncRNA sequencing and protein profiling analysis to identify ferroptosis-associated lncRNAs and proteins. qRT-PCR was used to analyze the expression of BDNF-AS and FBXW7 in GC tissues and adjacent normal tissues. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and coimmunoprecipitation (co-IP) assays were performed to investigate the interaction between BDNF-AS and its downstream targets. Finally, the function of BDNF-AS was validated in vivo . We demonstrated that BDNF-AS was highly expressed in GC and PM tissues. High BDNF-AS expression was positively related to GC progression and poor prognosis. Functionally, BDNF-AS overexpression protected GC cells from ferroptosis and promoted the progression of GC and PM. Mechanistically, BDNF-AS could regulate FBXW7 expression by recruiting WDR5, thus affecting FBXW7 transcription, and FBXW7 regulated the protein expression of VDAC3 through ubiquitination. Conclusively, our research demonstrated that the BDNF-AS/WDR5/FBXW7 axis regulates ferroptosis in GC by affecting VDAC3 ubiquitination. BDNF-AS might be a biomarker for the evaluation of GC prognosis and the treatment of GC.