GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance

• Published in: eLife Vol. 8
• Main Authors: Lee, Eugine, Wongvipat, John, Choi, Danielle, Wang, Ping, Lee, Young Sun, Zheng, Deyou, Watson, Philip A, Gopalan, Anuradha, Sawyers, Charles L
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 15.01.2019; eLife Sciences Publications, Ltd
• Subjects: Androgen Antagonists - pharmacology; Androgen receptors; Androgens; AR coactivator; AR signaling output; Benzamides; Cancer Biology; Cell Line, Tumor; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA, Neoplasm - metabolism; Drug resistance; Drug Resistance, Neoplasm - drug effects; enzalutamide; Flow cytometry; Genes; Genomes; Genomics; GREB1; Humans; Infections; intra-tumoral heterogeneity; Male; Neoplasm Proteins - metabolism; Nitriles; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Population; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Binding - drug effects; Receptors, Androgen - metabolism; Software; Transcription, Genetic - drug effects; Tumor cell lines; Tumors; New York; United States > US; intra-tumoral heterogeneity; GREB1; cancer biology; AR signaling output; human; AR coactivator; enzalutamide
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.41913

Genomic amplification of the androgen receptor ( ) is an established mechanism of antiandrogen resistance in prostate cancer. Here, we show that the magnitude of signaling output, independent of genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator . We demonstrate 100-fold heterogeneity in output within human prostate cancer cell lines and show that cells with high output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify as a gene responsible for high output. We show that is an target gene that amplifies output by enhancing DNA binding and promoting recruitment. knockdown in high output cells restores enzalutamide sensitivity . Thus, is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.