SEI1 complex silences p53 to drive myeloma progression.

SEI1 is overexpressed in multiple myeloma and correlates with poor prognosis. In this study, we identify SEI1 as a crucial driver of myeloma pathogenesis through a previously unrecognized mechanism: transcriptional inactivation of the tumor suppressor p53. Mechanistically, SEI1 forms a transcriptional complex with histone deacetylase 1 (HDAC1) and forkhead box C1 (FOXC1), which binds to the p53 promoter, decreases histone H3 lysine 27 acetylation (H3K27ac), and suppresses p53 transcription, thereby promoting myeloma cell proliferation. SEI1 enhances the stability of the HDAC1-FOXC1 interaction, further amplifying p53 repression. High-throughput virtual screening has identified tiludronate disodium as a potent inhibitor of FOXC1. Tiludronate disodium disrupts the HDAC1-FOXC1 interaction, restores H3K27ac enrichment and p53 expression, and suppresses myeloma growth both in vitro and in vivo, including a reduction of osteolytic lesions. These findings elucidate the SEI1/HDAC1/FOXC1/p53 axis as a critical driver of myeloma progression and identify tiludronate disodium as a potential therapeutic agent.