Transcriptome-wide identification of transcripts regulated by MBNL3 in hepatocellular carcinoma cells. Homo sapiens

Understanding the roles of splicing factors and splicing events during human tumorigenesis would open new avenues for targeted therapeutics. Here we identify an oncofetal splicing factor MBNL3, which indicates poor prognosis, and promotes hepatocellular carcinoma (HCC) tumorigenesis. Genetic MBNL3 inhibition almost completely abolishes HCC tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces PXN antisense transcript 1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, thereby inhibiting PXN mRNA translation. Whereas the transcript containing exon 4 preferentially binds to 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, thereby increasing PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN expression, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between oncofetal splicing factor, splicing event, and tumorigenesis, and establish splicing factors and splicing events would be potential therapeutic targets. Overall design: To identify transcripts regulated by MBNL3, we performed RNA sequencing using RNA retrieved from MBNL3 stably depleted and control SMMC-7721 cells.