Abstract 2856: GLI3-mediated HH regulates prostate cancer progression

Abstract

Abstract Although prostate cancer patients initially respond to androgen deprivation therapy, they eventually progress to lethal castration resistant prostate cancer (CRPC), characterized by restoration of the androgen receptor (AR) signaling despite castrate levels of circulating androgens. Mechanisms proposed to underlie CRPC include AR crosstalk with alternative signaling pathways. Among these, the Sonic hedgehog (SHH)Hedgehog (HH) pathway, an essential signaling axis in prostate development and homeostasis, has been implicated in prostate cancerCRPC progression. SHH pathway is regulated by transcription factors and effectors Glioma-associated oncogene family zinc finger (GLI) proteins 1, 2, and 3. Previous studies reported that GLI1 and GLI2 drive androgen-independent growth of prostate cancer by upregulating androgen-stimulated genes. However, whether and how GLI3 plays a role in prostate cancer progression remains unclear. In the present study, we investigated the role of GLI3 in the progression of prostate cancer cells. Like GLI2, GLI3 is the a downstream transcriptional factor effector of the SHH signaling pathway that can exist as a full-length activator form or a cleaved repressor form. Our data showed an increase in GLI3 expression in prostate cancer cells growing under androgen deprived conditions. Thuserefore, we hypothesize that androgen deprivation leads to activation of the SHH signaling pathway which consequently activates GLI3 to promote androgen-independent growth of prostate cancer cells. We showed that knockdown of GLI3 repressed while overexpression of GLI3 promoted androgen-independent growth of prostate cancer cells. GLI3 knockdown also resulted in regression of castration-resistant outgrowth of xenograft tumors in mice. Additionally, transcriptomic analysis of GLI3 knockdown cells revealed that the SHH signaling pathway and epithelial mesenchymal transition (EMT) genes are altered suggesting that GLI3 regulates androgen-independent growth of prostate cancer cells through canonical SHH signaling pathway and likely contributes to prostate cancer metastasis. Lastly, our data demonstrated a physical and functional relationship between GLI3 and AR suggesting a functional crosstalk between SHH signaling and AR signaling pathways in advanced prostate cancer. Citation Format: Thu Minh Duong, Marieke Oldenbroek Burleson, J J. Deng, T Qin, Das D, L-z Sun, T G. Boyer. GLI3-mediated HH regulates prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2856.