Anisomycin Induces Senescence and Death of Ovarian Cancer Stem Cells Through the MicroRNA‐340/SENP6/SUMOylation Pathway

ABSTRACT

Ovarian cancer remains a leading cause of gynecologic cancer mortality, in part due to the persistence of ovarian cancer stem cells (OCSCs) that drive tumor recurrence, metastasis, and drug resistance. Anisomycin, a natural antibiotic derived from Streptomyces coelicolor , has previously been shown to exert antitumor effects, but the mechanisms by which it targets OCSCs remain unclear. In this study, primary human OCSCs were isolated and treated with anisomycin to investigate its biological and molecular effects. Cell proliferation, apoptosis, migration, and colony formation were assessed in vitro, and tumorigenicity was evaluated in xenograft mouse models. Transcriptomic, biochemical, and molecular assays were performed to identify downstream pathways. Anisomycin treatment markedly inhibited proliferation and promoted senescence and cell death of OCSCs. Mechanistically, anisomycin induced upregulation of microRNA‐340, which in turn suppressed the deSUMOylating enzyme SENP6. This repression increased SUMOylation of key senescence‐related proteins, including p53 and p16, leading to stabilization of their expression and enforcement of cell‐cycle arrest. Overexpression of microRNA‐340 reproduced these effects, both in vitro and in vivo, confirming its central role in mediating anisomycin activity. Bioinformatic analyses further revealed that expression of SENP6 and senescence‐associated genes correlated with disease progression and patient survival in ovarian cancer cohorts. These findings identify a previously unrecognized epigenetic mechanism by which anisomycin induces senescence and death in OCSCs, suggesting that targeting the microRNA‐340/SENP6/SUMOylation pathway may represent a promising therapeutic approach.