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Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 ( SF3B1   R625H  ), but its functional effects and underlying molecular mechanisms remain largely unexplored. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous  Sf3b1   R625H   mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in  SF3B1 -wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of  SF3B1   R625H   were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the  SF3B1   R625H   allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1 R625H  promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1 R625H  and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the  SF3B1   R625H   mutation.

The SF3B1R625H mutation promotes prolactinoma tumor progression through aberrant splicing of DLG1