Exosomal AFAP1-AS1 promotes the growth, metastasis, and glycolysis of pituitary adenoma by preventing HuR degradation

Abstract

Background Exosomal long noncoding RNAs (lncRNAs), which are highly concentrated in tumor-derived exosomes, play a crucial role in modulating cellular behaviors such as cell proliferation, metastasis, and glycolysis by facilitating intercellular communication. Here, we elucidated the role and regulatory mechanism of tumor-derived exosomal lncRNAs in pituitary adenomas (PA). Methods We isolated exosomes from PA cells, then performed in vitro and in vivo assays to evaluate proliferation, metastasis, and glycolysis effects. Next, we conducted RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation and ubiquitination assays to investigate exosomal AFAP1-AS1’s potential downstream mechanism. Results Exosomes from PA cells augmented the proliferation, mobility, and glucose metabolism of PA cells. Particularly, actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1) was significantly enriched in these exosomes. Furthermore, exosomal AFAP1-AS1 not only stimulated growth, migration, invasion and glucose metabolism abilities of PA cells in vitro, but also promoted tumor metastasis in vivo. Additionally, exosomal AFAP1-AS1 markedly enhanced binding affinity between Hu antigen R (HuR) and SMAD specific E3 ubiquitin protein ligase 1 (SMURF1), resulting in HuR ubiquitination and degradation to upregulate HK2 and PKM2 expression. Moreover, HuR overexpression impaired exosomal AFAP1-AS1-mediated promotion of growth, metastasis and glycolysis effects. Conclusions These findings indicate that cancer-derived exosomal AFAP1-AS1 modulated SMURF1-mediated HuR ubiquitination and degradation to upregulate HK2 and PKM2 expression, thereby potentially contributing to the promotion of PA cell growth, metastasis, and glucose metabolism. Targeting the exosomal AFAP1-AS1 may be a potential strategy for the treatment of PA.