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.
Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N 6 -methyladenosine (m 6 A) modification is known to modulate pri-miRNA processing. However, whether m 6 A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m 6 A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m 6 A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m 6 A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m 6 A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What’s more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m 6 A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.
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