MASTL Promotes Hepatocellular Carcinoma Progression and Paclitaxel Resistance Through Mitotic Catastrophe

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options. Microtubule-associated serine/threonine kinase-like (MASTL), a pivotal regulator of Mitosis, remains poorly characterized in HCC. This study aimed to elucidate the clinical significance, biological functions, and molecular mechanisms of MASTL in HCC progression. Bioinformatics analysis of TCGA and ICGC datasets revealed MASTL overexpression correlated with advanced tumor stage and served as an independent prognostic factor. Functional studies demonstrated that MASTL knockdown significantly disrupts HCC cell proliferation, increases the incidence of abnormal mitotic events, and amplifies DNA damage, collectively driving mitotic catastrophe (MC) and subsequent cell death. Mechanistically, MASTL regulated paclitaxel sensitivity by modulating ENSA phosphorylation and PP2A-B55α activity, with PP2A-B55α knockdown reversing MASTL deficiency-induced MC. Transcriptional regulation analysis identified E2F1 as a direct activator of MASTL expression, confirmed by ChIP-qPCR and dual-luciferase reporter assays. These findings establish MASTL as a critical oncogene in HCC through the E2F1-MASTL-PP2A-B55α axis, suggesting its potential as both a prognostic biomarker and therapeutic target for HCC. Future studies should explore MASTL inhibitors in combination with conventional chemotherapy to overcome drug resistance in HCC patients.

DNA damage; MASTL; greatwall kinase; hepatocellular carcinoma; mitotic catastrophe.