GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen...

Area of Science:

• Oncology
• Molecular Biology
• Signaling Pathways

Background:

• The Sonic hedgehog (SHH) pathway's role in prostate cancer malignancy is known, but activation mechanisms remain unclear.
• GLI3, a SHH pathway effector, is implicated in prostate cancer progression.
• Speckle-type POZ protein (SPOP) mutations are found in prostate cancer and affect protein degradation.

Purpose of the Study:

• To elucidate the mechanisms of GLI3 activation in prostate cancer.
• To investigate the functional role of GLI3 in androgen receptor (AR)-positive prostate cancer, especially under androgen-depleted conditions.
• To identify therapeutic strategies targeting GLI3 in castration-resistant prostate cancer (CRPC).

Main Methods:

• Investigated GLI3 regulation by androgen deprivation and SPOP mutations.
• Assessed GLI3's necessity and sufficiency for prostate cancer cell growth and migration.
• Examined GLI3 and AR interaction and functional cooperation.
• Identified and validated an AR/GLI3 co-regulated gene signature.

Main Results:

• GLI3 is upregulated during androgen deprivation and stabilized by SPOP mutations, which impair its degradation.
• GLI3 is essential for the growth and migration of AR-positive prostate cancer cells, particularly in low-androgen conditions.
• GLI3 interacts with AR, promoting an AR-dependent gene program that drives castration-resistant tumor growth.
• A specific AR/GLI3 gene signature predicts castration-resistant metastatic prostate cancer and recurrence.

Conclusions:

• Hyperactivated GLI3 signaling, driven by SPOP mutations and androgen deprivation, promotes castration-resistant prostate cancer growth.
• Enhanced AR/GLI3 cross-talk is a key mechanism in CRPC development.
• GLI3 inhibitors represent a potential therapeutic strategy for CRPC.