Role of cell cycle-related gene SAC3 domain containing 1 as a potential target of nitidine chloride in hepatocellular carcinoma progression

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is at the forefront of the global spectrum of cancer incidence and mortality, with conventional therapies like tyrosine kinase inhibitors limited by resistance. Recent studies have highlighted the promising anticancer effects of nitidine chloride (NC) against HCC. SAC3 domain containing 1 (SAC3D1) is critical for centrosome replication and spindle formation. However, research on SAC3D1 in HCC and NC remains limited.

AIM

To investigate the mechanisms underlying SAC3D1’s role in HCC progression and evaluated its potential as a therapeutic target of NC.

METHODS

RNA sequencing (RNA-seq) identified SAC3D1 expression changes in HCC cells after NC treatment. Molecular docking was further employed to validate the direct binding between NC and SAC3D1. Additionally, HCC multicenter data (The Cancer Genome Atlas_GTEx, ArrayExpress), pathway analysis, Pearson correlation analysis and SAC3D1 in vitro knockdown experiments were integrated to explore the molecular mechanisms underlying SAC3D1's involvement in HCC progression.

RESULTS

RNA-seq showed that NC treatment significantly downregulated SAC3D1 expression [log₂(fold change) = - 0.95, P < 0.05], with molecular docking revealing that NC directly bound to SAC3D1 proteins (binding energy: -9.7 kcal/mol). Enrichment analysis showed that most pathways were closely related to the cell cycle. Pearson correlation analysis indicated that SAC3D1 and cell cycle genes were significantly positively correlated(correlation coefficient ≥ 0.3, P < 0.05). SAC3D1 knockdown inhibited HCC cell invasion, migration, and proliferation by arresting cells in the S and G2/M phases. Flow cytometry confirmed that after SAC3D1 knockdown, the early and total apoptosis percentage of HCC cells decreased, while the late apoptosis percentage increased.

CONCLUSION

As a potential target of NC, SAC3D1 may inhibit HCC progression through cell cycle regulation following its downregulation by NC.

Keywords: Hepatocellular carcinoma; SAC3 domain containing 1; Nitidine chloride; Cell cycle; Molecular docking

Core Tip: The role of SAC3 domain containing 1 (SAC3D1) in hepatocellular carcinoma (HCC) remains unclear. Through bioinformatic analysis, molecular docking techniques, and in vitro experiments, this study demonstrates for the first time that SAC3D1 serves as a novel target for nitidine chloride (NC), which previous studies have shown to have anti-HCC effects. Downregulation of SAC3D1 by NC may inhibit HCC progression by regulating the cell cycle, providing opportunities for novel therapeutic approaches in HCC treatment.