FOXM1 influences DNA methylation to augment TACC3 alternative splicing directed by KAT2A in hepatocellular carcinoma

<h4>Background/aims</h4>Hepatocellular carcinoma (HCC) is characterized by profound transcriptomic dysregulation, yet the mechanism(s) by which DNA methylation is coordinated with chromatin modifications to regulate alternative splicing during tumorigenesis remains poorly understood.<h4>Methods</h4>Using prospectively paired multi-omics data obtained from metabolic dysfunction-associated steatotic liver disease (MASLD)-HCC patients and coupled with a premalignant MASLD cohort, we have uncovered a previously unrecognized gene-regulatory axis centered on TACC3 isoform-switching.<h4>Results</h4>In the non-tumoral context, the TACC3-201 isoform directly engages the histone acetyltransferase KAT2A to coordinate the regulation of NOTCH4 signaling. In HCC, this regulatory axis is disrupted whereby FOXM1 overrides DNMT1-mediated methylation, upregulating TACC3, and decoupling TACC3 from the KAT2A-associated NOTCH4 co-expression module. This rewiring is licensing tumor-specific cell-cycle progression and epigenetic plasticity. Thus, FOXM1 reshapes the TACC3-KAT2A interaction, while DNMT1 drives context-dependent DNA methylation, activating the CDK1-inhibitory kinase PKMYT1.<h4>Conclusions</h4>We uncovered TACC3-KAT2A as an emerging regulatory axis caused by alternative splicing in HCC and propose FOXM1-driven TACC3 inhibition to synergistically disrupt mitotic fidelity and transcriptional regulation, potentially offering new therapeutic avenues for HCC with reduced toxicity to the normal liver.