Related Experiment Video
Updated: Oct 18, 2025
Generation of Tumor Organoids from Genetically Engineered Mouse Models of Prostate Cancer
Published on: June 13, 2019
GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen
Marieke Burleson1, Janice J Deng2, Tai Qin2
1Department of Molecular Medicine, UT Health San Antonio, San Antonio, Texas.
Abstract:
Although the Sonic hedgehog (SHH) signaling pathway has been implicated in promoting malignant phenotypes of prostate cancer, details on how it is activated and exerts its oncogenic role during prostate cancer development and progression is less clear. Here, we show that GLI3, a key SHH pathway effector, is transcriptionally upregulated during androgen deprivation and posttranslationally stabilized in prostate cancer cells by mutation of speckle-type POZ protein (SPOP). GLI3 is a substrate of SPOP-mediated proteasomal degradation in prostate cancer cells and prostate cancer driver mutations in SPOP abrogate GLI3 degradation. Functionally, GLI3 is necessary and sufficient for the growth and migration of androgen receptor (AR)-positive prostate cancer cells, particularly under androgen-depleted conditions. Importantly, we demonstrate that GLI3 physically interacts and functionally cooperates with AR to enrich an AR-dependent gene expression program leading to castration-resistant growth of xenografted prostate tumors. Finally, we identify an AR/GLI3 coregulated gene signature that is highly correlated with castration-resistant metastatic prostate cancer and predictive of disease recurrence. Together, these findings reveal that hyperactivated GLI3 promotes castration-resistant growth of prostate cancer and provide a rationale for therapeutic targeting of GLI3 in patients with castration-resistant prostate cancer (CRPC). IMPLICATIONS: We describe two clinically relevant mechanisms leading to hyperactivated GLI3 signaling and enhanced AR/GLI3 cross-talk, suggesting that GLI3-specific inhibitors might prove effective to block prostate cancer development or delay CRPC.
Insights
GLI3 protein stabilizes during androgen deprivation in prostate cancer, promoting tumor growth and migration. Targeting GLI3 may treat castration-resistant prostate cancer.
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.
Related Concept Videos
02:23Abnormal Proliferation
01:23Negative Regulator Molecules