RESUMO
Prostate cancer is a disease that depends on androgenic stimulation and is thus commonly treated with androgen deprivation therapy (ADT). ADT is highly successful initially; however, patients inevitably relapse at which point the cancer grows independently of androgens and is termed castration-resistant prostate cancer (CRPC). CRPC develops through various mechanisms, one of these being crosstalk of the androgen receptor (AR) signaling pathway with other signaling pathways. Congruently, prior work has shown that androgen deprivation induces SHH signaling, which subsequently promotes activation of AR-dependent gene expression to promote cell growth. Mechanistically, this crosstalk involves a physical interaction between AR and components of SHH signaling, specifically proteins of the GLI transcription factor family. These findings thus suggest that activation of SHH signaling could promote the recurrence of cell growth in the absence of androgens to ultimately lead to progression towards CRPC. In this study, we have investigated this mechanism in a subset of prostate cancer that harbors genetic alterations within the Mediator subunit 12 (MED12). We found that loss of MED12 promotes the expression of GLI3 target genes which subsequently drives excessive cell growth in the absence of androgens. Thus, we conclude that genetic alterations within MED12 promote CRPC through hyperactivated GLI3 dependent sonic hedgehog signaling.
RESUMO
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.
