ALKBH5/IGF2BP1-mediated m6A demethylation of TRIM37 promotes pancreatic cancer tumorigenesis and glycolysis by mediating RBMX degradation

The upregulation of the ubiquitin ligase TRIM37 is associated with an adverse prognosis in pancreatic ductal adenocarcinoma (PDAC). This study investigates the mechanism and oncogenic consequence of TRIM37 upregulation in PDAC development. TRIM37 expression was assessed by qPCR and Western blotting. The effects of TRIM37 knockdown and overexpression on cell proliferation, colony formation, stemness capacity was investigated through in vitro assays, and the role in PDAC was evaluated through vivo experiments. RNA immunoprecipitation assay and Actinomycin D assay were performed to detect the mechanism of TRIM37 upregulation. The TRIM37 and RBMX interaction were determined through co-immunoprecipitation and immunofluorescence. We identified TRIM37 as a critical oncoprotein in PDAC, and its overexpression was strongly correlated with poor prognosis. As a ubiquitin ligase, TRIM37 targets the tumor suppressor RBMX for proteasomal degradation, promoting glycolytic reprogramming and driving aggressive cancer phenotypes, including enhanced proliferation, migration, and stemness. Furthermore, we found that the ALKBH5-IGF2BP1 axis promotes TRIM37 expression by controlling N6-methyladenosine (m6A) modification of TRIM37 mRNA and enhancing its transcript stability. Our findings establish the ALKBH5/IGF2BP1-TRIM37-RBMX signaling axis as a pivotal driver of PDAC progression, highlighting the intersection of m6A modification, ubiquitin signaling, and metabolic reprogramming. These findings may provide potential therapeutic avenues for this intractable malignancy.