PSMD14 Transcriptionally Activated by MEF2A Promotes Pancreatic Cancer Development by Upregulating SPON2 Expression.

Abstract

Proteasome 26S subunit non-ATPase 14 (PSMD14) plays a pro-carcinogenic role in various cancers. However, its specific effects and mechanisms in pancreatic cancer (PC) remain unclear. We aimed to assess the function and mechanism of PSMD14 in PC. Fifteen paired pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent non-tumorous tissues were clinically obtained. Cell proliferation, migration, and invasion were assessed using colony formation, scratch, and Transwell assays. The interaction between the MEF2A transcription factor and the PSMD14 promoter verified by chromatin immunoprecipitation (ChIP) or dual luciferase assay. The interaction between RBM15B and SPON2 mRNA was validated by RNA immunoprecipitation (RIP) assay. The interaction between the proteins PSMD14 and RBM15B was detected by co-immunoprecipitation (Co-IP) assay. The m6A level of SPON2 was detected by methylated RNA immunoprecipitation (MeRIP, a common method for detecting m6A levels of mRNAs). The ubiquitination level of RNA-binding motif protein 15B (RBM15B) was detected using Co-IP. The role of PSMD14 in PC was further explored subcutaneous and lung metastasis models. PSMD14 was upregulated in PDAC tissues. PSMD14 knockdown inhibited PC cell viability, proliferation, migration, and invasion. MEF2A transcriptionally activated PSMD14 expression. PSMD14 knockdown promoted the ubiquitination degradation of RBM15B. Additionally, PSMD14 enhanced SPON2 mRNA stability through RBM15B-mediated m6A modification. SPON2 overexpression impaired the effect of knockdown PSMD14. Finally, PSMD14 knockdown in PC arrested tumor growth and lung metastasis. PSMD14, transcriptionally activated by MEF2A, promotes the de-ubiquitination of RBM15B, which upregulates SPON2 expression in an m6A-RBM15B-dependent manner, thereby facilitating PC proliferation, migration, and invasion.