Suppression of FOXO1 activity by SIRT1-mediated deacetylation weakening the intratumoral androgen autocrine function in glioblastoma.

in Cancer gene therapy by Yuanchi Cheng, Zhijun Xiao, Weijia Cai, Ting Zhou, Zhen Yang

TLDR

  • This study reveals that elevated androgens in GBM patients' brains come from tumor autocrine, and that overexpressing Sirt1 can effectively decrease brain androgen levels and delay tumor progression.

Abstract

Elevated levels of androgens in the brain accelerate tumor progression in patients with glioblastoma (GBM). Despite current research efforts concentrating on decreasing peripheral androgens to improve GBM prognosis, results have not met expectations. Herein, we aim to elucidate the source of increased androgen levels in the brains of GBM patients and investigate whether lowering it can improve the prognosis of GBM patients. The Elisa was employed to measure androgen levels. The effects of androgens on U87 cells were evaluated using CCK-8 assays, clone formation assays, wound healing assays, and migration/invasion assays. RNA sequencing, RT-qPCR and Western blotting were performed to assess the expression levels of steroid enzymes, tumor drug resistance, Sirt1, FOXO1genes and proteins. Co-immunoprecipitation (Co-IP) assays were conducted to investigate the interactions and acetylation levels between Sirt1 and FOXO1. Lentiviral transfection was utilized to establish stable cell lines. Furthermore, an in vivo murine subcutaneous tumor model was established to further confirm the role of Sirt1 in tumor progression. We found androgen levels in the cerebrospinal fluid of GBM patients were higher than in the periphery, contrasting with healthy individuals. Additionally, the steroid enzymes in GBM cells were upregulated. Reducing peripheral androgens compensatorily enhances GBM androgen synthesis capacity (CYP17A1, CYP11A1, SRD5A2) and chemo-resistance (ABCB11, BIRC3, FGF2, NRG1), while the levels of androgens in the brain remain consistently high. The above results indicate that the increased androgens in the brain of GBM patients are self-secreted. Further investigations demonstrate that the transcription factor FOXO1 in GBM is regulated by silent information regulator 1 (Sirt1) through deacetylation, leading to enhanced androgen synthesis capacity in vivo and in vitro. Overexpressing Sirt1 significantly lowers brain androgen levels and delays tumor progression in mouse models. Compared to conventional finasteran therapy, the targeted-Sirt1 results in lower brain androgen levels and smaller tumor volumes. Our findings provide evidence that the elevated androgens in the brain of GBM patients came from tumor autocrine. Overexpression of Sirt1 reduces FOXO1 acetylation, lowers androgen synthesis enzyme levels, and effectively decreases brain androgen levels, thereby delaying tumor progression.

Overview

  • The study aims to investigate the source of elevated androgen levels in GBM patients' brains and to test whether lowering it can improve their prognosis.
  • The researchers used ELISA to measure androgen levels, and various biological assays to evaluate the effects of androgens on U87 cells and to assess the expression levels of specific genes and proteins.
  • The primary objective is to elucidate the source of increased androgen levels in the brains of GBM patients and to explore whether lowering it can improve GBM prognosis.

Comparative Analysis & Findings

  • The study found elevated androgen levels in the cerebrospinal fluid of GBM patients compared to healthy individuals, and upregulated steroid enzymes in GBM cells.
  • Reducing peripheral androgens compensatorily enhances GBM androgen synthesis capacity, while the levels of androgens in the brain remain consistently high.
  • Overexpressing Sirt1 significantly lowers brain androgen levels and delays tumor progression in mouse models, suggesting that Sirt1 can be a potential therapeutic target.

Implications and Future Directions

  • The study's findings provide evidence that the elevated androgens in the brain of GBM patients come from tumor autocrine, and overexpression of Sirt1 can effectively decrease brain androgen levels and delay tumor progression.
  • Future studies can explore the potential therapeutic applications of Sirt1 overexpression in GBM treatment, and investigate the effects of Sirt1 overexpression on other biological processes and pathways.
  • The study highlights the need for further research on the role of androgens in GBM progression and on the therapeutic potential of Sirt1-targeted therapies.
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