Abstract 5239: Gli is a primary driver of prostate cancer cell growth

Abstract Canonical Hedgehog signaling is a Smoothened- (Smo-) driven process that activates transcription from Gli proteins. However, we have shown that Hedgehog is activated in prostate cancer (PCa) cells by a non-canonical, non-Smo-dependent process mediated by the binding of transcriptionally active androgen receptors (AR) to the protein processing domain on Gli2/3. This binding competes with β-TrCP, and protects Gli3 (the predominant Gli isoform in PCa cells) from cleavage to its truncated repressor form (Gli3R). Our observations are consistent with the idea that AR transcriptional activity (mediated by liganded full-length AR or by truncated ARs) is effectively coupled to Gli activity in PCa. Here we present our evidence that Gli is the primary driver of PCa cell growth and that suppression of Gli transcriptional activity or interference with AR binding to Gli (using a decoy peptide) is a strong growth suppressor of androgen-dependent (AD) and -independent (AI) PCa cell lines. Gli transcription was inhibited by GANT61 or HPI-1 or by exogenous overexpression of a Gli3R cDNA. Each of these conditions significantly suppressed the growth of LNCaP parental (AD) and LNCaP-AI cells. Knockdown of Gli3 with siRNA decreased growth of a wide variety of PCa cell lines up to 75%. Finally, a decoy peptide (270aa) containing the Gli2 AR binding site displaced Gli3 from AR complexes, increased the levels of Gli3R and significantly suppressed growth of AI cell lines. Collectively, our data supports the idea that androgen-driven growth of PCa is a result of non-canonical activation of Gli and that interference with Gli binding to DNA or with the Gli-AR interaction is a means for suppressing PCa cell growth. Citation Format: Na Li, Jackson Moore, Sarah Troung, Mannan Nouri, Jane Foo, Ralph Buttyan. Gli is a primary driver of prostate cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5239.