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

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.

SUBMITTER: Burleson M

PROVIDER: S-EPMC9258906 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Burleson Marieke M Deng Janice J JJ Qin Tai T Duong Thu Minh TM Yan Yuqian Y Gu Xiang X Das Debodipta D Easley Acarizia A Liss Michael A MA Yew P Renee PR Bedolla Roble R Kumar Addanki Pratap AP Huang Tim Hui-Ming TH Zou Yi Y Chen Yidong Y Chen Chun-Liang CL Huang Haojie H Sun Lu-Zhe LZ Boyer Thomas G TG

Molecular cancer research : MCR 20211005 1

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 SP ...[more]

PMID: 34610962

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Project description:Although androgen deprivation therapy triggers a rapid response in men with metastatic prostate cancer, most patients eventually progress to lethal castration resistant prostate cancer (CRPC) characterized by androgen receptor (AR)-dependent tumor growth despite castrate levels of circulating androgens. Current treatment options for CRPC remain limited and non-curative, rendering improved outcomes dependent on deeper mechanistic insight and new therapeutic targets. In this RNA sequencing study we profiled the transcriptomes of SPOP WT and mutant LNCaP cells before and after androgen deprivation by RNA-sequencing. Using standard criteria (minimum 2-fold change), we identified 981 genes that were differentially expressed in SPOP mutant vs SPOP WT LNCaP cells grown in the absence of androgens . Strikingly, a significant fraction (595 or ~60%) of these genes overlapped with genes (3510 in number) differentially expressed as a function of androgen in WT LNCaP cells, indicating partial restoration of AR signaling in SPOP mutant cells following androgen withdrawal. To determine the contribution of GLI3 to this process, we performed RNA-sequencing following GLI3 knockdown in androgen-deprived SPOP mutant LNCaP cells. Among the 595 androgen-responsive genes in LNCaP cells whose hormone-independent expression is regulated by SPOP 187 (or ~31%) are also regulated by GLI3, thus revealing a prominent role for GLI3 in restoration of AR signaling in SPOP mutant cells following androgen withdrawal. Enrichment analysis using Gene Ontology Biological Processes revealed these 187 GLI3-regulated genes to be prominently linked with “chromosome segregation”, “DNA replication”, “transcriptional regulation of in G1/S transition”, “regulation of mitotic cell cycle”, and “chromatin silencing” among others, suggesting possible molecular genetic bases for androgen independent growth of SPOP mutant cells. Taken together, these findings indicate that SPOP mutant prostate cancer cells acquire robust androgen-independent growth through reestablishment of an AR signaling axis that involves functional crosstalk with the SHH/GLI3 pathway.

Dataset Information

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

Publications

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

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