YY1: a key regulator inhibits gastric cancer ferroptosis and mediating Apatinib-resistance

Abstract

Abstract Background Gastric cancer (GC) is one of the most common and lethal cancers worldwide. Apatinib, a preoperative neoadjuvant therapy, has limited efficacy in GC patients with high YY1 expression. YY1 is associated with poor prognosis, drug resistance and metastasis in GC, but its mechanisms are unclear. Results We observed that higher YY1 expression levels were associated with lower postoperative progression-free survival (PFS) and disease-specific survival (DSS) rates based on the TCGA analysis. Moreover, YY1 expression was found to be an independent indicator of DSS in GC patients. Additionally, YY1 expression was significantly higher in tumor tissues compared to adjacent normal tissues. Bioinformatics analysis revealed significant differentially expressed genes (DEGs), transcriptional targets, transcription factors, and co-expressed genes related to YY1. Through LASSO Cox analysis, we identified Transferrin as a potential key protein regulated by YY1, and its high expression was correlated with adverse DSS and PFS outcomes. Further analysis showed that YY1 regulated the activity of the p53 signaling pathway and ferroptosis in GC cells. The study also revealed that YY1 overexpression suppressed immune cell infiltration in GC tumors. Furthermore, the study demonstrated that YY1 overexpression inhibited GC cell ferroptosis and mediated Apatinib resistance through the p53 signaling pathway. IFN-a reverses Apatinib resistance and immune suppression in GC tissues. Conclusions Our findings suggest that YY1 plays a crucial role in GC progression and prognosis and may serve as a potential therapeutic target for improving patient outcomes.