<scp>TONSL</scp> Promotes Hepatocellular Carcinoma Progression by Inhibiting Apoptosis Through Homologous Recombination Repair

Hepatocellular carcinoma (HCC) is an extremely aggressive type of cancer with a poor prognosis and is often associated with amplification of chromosome 8q. Tonsoku-like DNA repair protein (TONSL) gene, located on 8q, plays a role in repairing DNA double-strand breaks. However, its functional relevance in HCC is not yet fully understood. In this study, we investigated the biological significance of TONSL in HCC progression. Analyses of public datasets and clinical specimens revealed that TONSL expression was markedly elevated in tumor tissues. TONSL levels showed a positive correlation with copy number variation and high levels were significantly associated with unfavorable patient outcomes. Functional assays demonstrated that TONSL knockout substantially reduced cell growth and increased apoptosis. Mechanistically, loss of TONSL impaired the recruitment of RAD51 to DNA damage sites, resulting in defective homologous recombination repair and enhanced apoptotic activity. Furthermore, TONSL-knockout HCC cells showed increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitor. In a xenograft model, tumors generated from TONSL-knockout cells exhibited significantly reduced growth, underscoring the importance of TONSL in promoting HCC progression. Collectively, these findings indicate that TONSL facilitates HCC development by supporting RAD51-mediated DNA repair and suppressing apoptosis, and its elevated expression serves as a marker of poor prognosis. Thus, TONSL represents a promising biomarker of tumor aggressiveness and a potential therapeutic target in HCC.