Halorotetin B, A Novel Terpenoid Compound Derived from Marine Ascidian, Suppresses Tumor Growth by Targeting the Cell Cycle Regulator UBE2C.

Screening and identification of novel small-molecule have proven to be effective strategies in addressing the growing threat of cancer to human health. In this study, a novel natural terpenoid compound, Halorotetin B, is identified from the edible ascidian Halocynthia roretzi. Halorotetin B is shown to significantly inhibit tumor growth both in vitro and in vivo. Mechanistically, the E2 ubiquitin-conjugating enzyme C (UBE2C) is identified as a direct binding target of Halorotetin B through a combination of the peptide-centric local stability assay and the omics-based target enrichment and ranking. Further investigations reveal that Halorotetin B binding to UBE2C induced M phase cell cycle arrest by inhibiting the ubiquitin-mediated degradation of key cell cycle regulators, including cyclin B1 and securin, ultimately leading to tumor cell senescence. These findings suggest that Halorotetin B, as a novel cell cycle inhibitor targeting UBE2C, holds strong potential for development into ascidian-derived therapeutics for cancer treatment.