Super enhancer-regulated lncRNA LINC01089 induces alternative splicing of DIAPH3 to drive hepatocellular carcinoma metastasis.

Hepatocellular carcinoma (HCC) is one of the most lethal neoplasms and has a 5-year survival rate of only 18% in patients with metastatic diseases. Epigenetic modifiers and alterations, including histone modifications, long noncoding RNAs (lncRNAs), RNA alternative splicing, and N6-methyladenosine (m6A) modification, are key regulators of HCC development, highlighting the importance of understanding the crosstalk between these biological processes. In the present study, we identified LINC01089 as a super enhancer (SE)-driven lncRNA that promotes epithelial-mesenchymal transition (EMT), migration, invasion and metastasis of HCC cells in vivo and in vitro. The transcription factor E2F1 bound to a LINC01089 SE, promoting LINC01089 transcription and overexpression. LINC01089 interacted with hnRNPM and led to hnRNPM-mediated skipping of DIAPH3 exon 3. Knockdown of LINC01089 increased the inclusion of DIAPH3 exon 3, which contains an important m6A-modification site that is recognized by IGF2BP3 to increase DIAPH3 mRNA stability. Thus, LINC01089 loss increased DIAPH3 protein levels, which suppressed the ERK/Elk1/Snail axis and inhibited EMT of HCC cells. In conclusion, this study revealed crosstalk between different epigenetics modifiers and alterations that drives HCC progression and identified LINC01089 as a potential prognostic marker and therapeutic target for HCC.