@article{646e3025dede4768bad4450d95f93594,
title = "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).",
author = "Marieke Burleson and Deng, {Janice J.} and Tai Qin and Duong, {Thu Minh} and Yuqian Yan and Xiang Gu and Debodipta Das and Acarizia Easley and Liss, {Michael A.} and {Renee Yew}, P. and Roble Bedolla and Kumar, {Addanki Pratap} and {Hui-Ming Huang}, Tim and Yi Zou and Yidong Chen and Chen, {Chun Liang} and Haojie Huang and Sun, {Lu Zhe} and Boyer, {Thomas G.}",
note = "Funding Information: This work was supported by a pilot grant from the Institute for Integration of Medicine & Science/Clinical Translational Science Award (to L. Sun), Cancer Prevention and Research Institute of Texas (CPRIT) awards RP120290-IIRA (to L. Sun) and RP140435-HIHRRA (to T. Boyer), and National Cancer Institute Cancer Center Support Grant P30 CA054174 (Optical Imaging, Next Generation Sequencing, and Biostatistics & Bioinformatics Shared Resources). M. Burleson and A. Easley were supported by NIH training grant T32CA148724. M. Burelson, T.M. Duong, and X. Gu were supported by CPRIT Research Training Program grants RP140105 and RP170345. T. Qin was supported by a fellowship from Xiangya School of Medicine, Central South University, Hunan, China. Funding Information: J.J. Deng reports grants from University of Texas Health Science Center at San Antonio, Cancer Prevention and Research Institute of Texas, National Cancer Institute, and Cancer Prevention and Research Institute of Texas, during the conduct of the study. T. Qin reports grants from University of Texas Health Science Center at San Antonio, Cancer Prevention and Research Institute of Texas, National Cancer Institute, and Cancer Prevention and Research Institute of Texas, during the conduct of the study. L. Sun reports grants from University of Texas Health Science Center at San Antonio, Cancer Prevention and Research Institute of Texas, National Cancer Institute, and Cancer Prevention and Research Institute of Texas, during the conduct of the study. T.G. Boyer reports grants from Cancer Prevention and Research Institute of Texas, National Cancer Institute, and National Institutes of Health during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research Inc.. All rights reserved.",
year = "2022",
month = jan,
doi = "10.1158/1541-7786.MCR-21-0108",
language = "English (US)",
volume = "20",
pages = "62--76",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "1",
}