Hypoxia‐Induced circPRELID2 Promotes Gastric Cancer Metastasis by Facilitating ZEB2 Translation via PCBP1 O‐GlcNAcylation

Circular RNAs (circRNAs) are involved in the occurrence and development of various carcinomas. However, the biogenesis, function and underlying mechanism of hypoxia-induced circRNA in gastric cancer (GC) are poorly understood. Here, a novel circRNA, circPRELID2, which is upregulated by HIF1A under hypoxic conditions, is identified. circPRELID2 is highly expressed in GC tissues, and positively correlates with lymph node invasion, vascular invasion in GC patients. Elevated circPRELID2 promotes the epithelial-mesenchymal transition (EMT) and metastasis of GC cells both in vitro and in vivo under hypoxic conditions. Mechanistically, HIF1A directly binds to the PRELID2 promoter to transcriptionally increase the expression of PRELID2 pre-mRNA in response to hypoxia. Moreover, protein kinase DYRK1A mediates SFPQ phosphorylation to promote the interaction between SFPQ and SAM68, further forming a DYRK1A-SFPQ-SAM68 ternary complex. Subsequently, the DYRK1A-SFPQ-SAM68 complex binds to Alu-containing introns flanking the circPRELID2-forming exons in the PRELID2 pre-mRNA to promote circPRELID2 circularization. Furthermore, circPRELID2 interacts with PCBP1 and promotes the cytoplasmic retention of PCBP1. CircPRELID2 enhances OGT-mediated PCBP1 O-GlcNAcylation at Threonine 99 site in the cytoplasm, which disrupts the binding of PCBP1 to the 3'-UTR of ZEB2, resulting in the reversal of ZEB2 translation silencing, and ultimately promoting the EMT and metastasis of GC cells. These findings reveal a new regulatory mechanism of circRNA biogenesis, and also uncover that circPRELID2 participates in the translation of ZEB2 during GC metastasis via the modulation of PCBP1 O-GlcNAcylation, which provides a promising prognostic biomarker and therapeutic target for GC metastasis.