DAZAP1 promotes cancer progression and chemotherapy resistance by stabilizing PIN1 protein in gastric cancer.

Gastric cancer (GC) continues to be a fatal disease globally, largely due to the lack of dependable molecular indicators enabling early diagnosis and therapeutic intervention. Single-cell transcriptomic analysis revealed significant enrichment of DAZAP1 in proliferating and malignant gastric epithelial cells. Using a combined analysis of single-cell and bulk RNA-seq datasets, we further recognized DAZAP1 as a putative oncogene correlated with poor clinical outcomes in GC. Functional experiments demonstrated that DAZAP1 promotes tumor proliferation, cell cycle progression, and chemotherapy resistance in vitro and in vivo. Mechanistically, DAZAP1 bound and stabilized USP34 mRNA, leading to increased USP34 protein expression, which in turn mediated the deubiquitination and stabilization of the oncoprotein PIN1. This subsequently resulted in activation of the MAPK signaling pathway, driving GC progression and chemoresistance. Furthermore, we revealed that DAZAP1 expression is post-transcriptionally regulated by m6A modification through the demethylase ALKBH5, which protects DAZAP1 mRNA from YTHDF2-mediated degradation. Collectively, our findings establish the ALKBH5/DAZAP1/USP34/PIN1/MAPK axis as a key regulatory mechanism in gastric tumorigenesis and chemoresistance, underscoring DAZAP1 as a promising candidate for therapeutic and diagnostic applications in GC.