Natural Product Toosendanin Suppresses the Malignant Development of Skin Melanoma by Targeting BNC2 for Degradation.

Toosendanin (TSN) is a highly potent natural anticancer compound derived from the fruit of Fructus Meliae Toosendan. In this study, TSN inhibited melanoma cell proliferation and cell-cycle progression, induced apoptosis, and suppressed metastasis in both in vitro and in vivo models. TSN is a potent PI3K inhibitor; here, we identify basonuclin 2 (BNC2) as a transcription factor critically involved in TSN's suppression of PIK3CA transcription in melanoma cells. In clinical samples and melanoma datasets, BNC2 expression is substantially elevated in skin cutaneous melanoma and correlates with poor patient metastasis. Functional studies demonstrate that BNC2 promotes melanoma cell proliferation and migration. TSN directly binds to BNC2 and CRBN, the substrate receptor subunit of the E3 ubiquitin ligase complex, acting as a molecular glue to induce ubiquitin-dependent degradation of BNC2 and subsequent downregulation of PIK3CA transcription. TSN nanoliposome encapsulation improves cellular uptake, tumor targeting, and anti-metastatic efficacy of TSN in vivo. These findings reveal a context-dependent oncogenic function of BNC2 in melanoma, contrasting with its previously described tumor-suppressive roles in other cancers, and establish TSN as a small-molecule degrader of BNC2 with therapeutic potential for melanoma.