Suppression of FOXO1 Activity by SIRT1-Mediated Deacetylation Weakening the Intratumoral Androgen Autocrine Function in Glioblastoma

This study investigates the source of elevated androgen levels in the brains of glioblastoma (GBM) patients and explores the potential of targeting these levels to improve prognosis. The research reveals that androgens in GBM patients are self-secreted by the tumor, with higher levels found in the cerebrospinal fluid compared to the periphery. The study demonstrates that the transcription factor FOXO1 is regulated by Sirt1 through deacetylation, which enhances androgen synthesis. Overexpressing Sirt1 reduces FOXO1 acetylation, decreases androgen synthesis enzyme levels, and effectively lowers brain androgen levels, thereby delaying tumor progression. In mouse models, targeted Sirt1 therapy results in lower brain androgen levels and smaller tumor volumes compared to conventional finasteride therapy. These findings suggest that targeting Sirt1 could be a promising strategy for managing GBM by reducing intratumoral androgen levels.