Oncogenic potential of truncated-Gli3 via the Gsk3β/Gli3/AR-V7 axis in castration-resistant prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Androgen receptor (AR) activation and Hh/Gli signaling are crucial in castration-resistant prostate cancer (CRPC).
• Resistance to AR-targeted therapies is a major clinical challenge in CRPC.
• The role of Gli3, particularly truncated Gli3 (t-Gli3), in CRPC progression is not well understood.

Purpose of the Study:

• To investigate the novel role of t-Gli3 in CRPC progression.
• To elucidate the mechanism of t-Gli3 activation and its regulation by the Gsk3β/AR-V7 axis.
• To evaluate the therapeutic potential of targeting Gsk3β and Gli3 in CRPC.

Main Methods:

• Investigated Gli3 regulation and activation mechanisms.
• Utilized Gsk3β knockdown (Gsk3β KD) in CRPC cell lines and in vivo mouse models.
• Performed RNA-seq and Gene Set Enrichment Analysis (GSEA).
• Assessed the efficacy of Gsk3β inhibitors, anti-Smo, anti-Gli1, and Gli3-targeting agents.

Main Results:

• Identified a Smo-independent mechanism for t-Gli3 activation, dependent on androgen receptor variant 7 (AR-V7).
• Gsk3β activation generates t-Gli3; Gsk3β inhibition promotes full-length Gli3 accumulation.
• Gsk3β KD reduced CRPC cell proliferation, induced apoptosis, and inhibited tumor growth in vivo.
• GSEA revealed apoptosis and tumor suppressor gene enrichment, with oncogenic pathway downregulation.
• Combination therapy (Gsk3β inhibitor with anti-Smo or Gli1) and sole Gli3 targeting effectively inhibited CRPC growth.

Conclusions:

• t-Gli3 plays a significant role in CRPC progression.
• The Gsk3β/t-Gli3/AR-V7 axis represents a novel therapeutic target for CRPC.
• Targeting Gli3, particularly t-Gli3, demonstrates significant anti-cancer effects in CRPC.