PPM1G‐mediated TBL1X mRNA splicing promotes cell migration in hepatocellular carcinoma

Abstract The progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor‐related genes. Identification of the tumor‐specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome‐wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six‐skipping transcript of TBL1X as an onco‐splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X‐S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half‐life of the TBL1X‐S transcript. Both PPM1G and TBL1X‐S exhibited metastasis‐promoting phenotypes, with PPM1G‐driven metastasis in HCC being partially dependent on TBL1X‐S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X‐S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial‐mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X‐S in tumor metastasis. The PPM1G/TBL1X‐S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.