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Med12 Mutations Promote Castration Resistant Prostate Cancer through Hyperactivated GLI3/SHH Signaling

Prostate cancer is the highest diagnosed and second most common cause of cancer death among US men. The onset and progression of prostate cancer is critically dependent upon androgens through their interaction with the androgen receptor (AR). Accordingly, it has long been established that androgen deprivation therapy leads to prostate cancer regression. Though androgen deprivation therapies are initially highly successful, most patients eventually suffer from recurrence of the disease in the form of castration resistant prostate cancer (CRPC). Currently there is no effective treatment for CRPC thereby highlighting the compelling need to address resistance mechanisms for patients that suffer from this lethal disease. Sonic hedgehog (SHH) signaling is a stromal‐epithelial interacting pathway that is critical for prostate development and cell growth. SHH signaling is induced by androgen deprivation thereby leading to re‐activation of AR target genes to promote prostate cancer cell growth in the absence of androgens. Furthermore, AR interacts with GLI proteins, downstream effectors in the SHH pathway. Therefore, GLI3‐dependent SHH signaling in androgen deprived cells could promote re‐activation of AR target genes and consequently lead to CRPC. It is currently unknown how GLI3‐dependent SHH signaling is induced in CRPC. In this study we show that stabilized GLI3 leads to the induction of GLI3‐dependent SHH signaling in prostate cancers that harbor mutations in MED12. MED12 is an Xq13‐encoded 230 kDa subunit of the RNA pol II transcriptional Mediator that has been found to be mutated in ~5% of prostate cancers. Through stable knockdown and luciferase assays, we show that MED12 mutations disrupt a Mediator‐imposed constraint on GLI3‐dependent SHH signaling. Furthermore, through stable knockdown and xenograft studies, we show that stable GLI3 is critically dependent for CRPC growth. The results of our study therefore indicate that prostate cancer patients with MED12 mutations relapse to CRPC after androgen deprivation therapy by hyperactivating the GLI3 dependent SHH signaling pathway. Overall, this study provides critical insight into possible treatment strategies for prostate cancer patients with MED12 mutations by using the GLI3/SHH signaling axis as a therapeutic target.