An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

• Published in: Nature cell biology Vol. 23; no. 9; pp. 1023 - 1034
• Main Authors: Davies, Alastair, Nouruzi, Shaghayegh, Ganguli, Dwaipayan, Namekawa, Takeshi, Thaper, Daksh, Linder, Simon, Karaoğlanoğlu, Fatih, Omur, Meltem E., Kim, Soojin, Kobelev, Maxim, Kumar, Sahil, Sivak, Olena, Bostock, Chiara, Bishop, Jennifer, Hoogstraat, Marlous, Talal, Amina, Stelloo, Suzan, van der Poel, Henk, Bergman, Andries M., Ahmed, Musaddeque, Fazli, Ladan, Huang, Haojie, Tilley, Wayne, Goodrich, David, Feng, Felix Y., Gleave, Martin, He, Housheng Hansen, Hach, Faraz, Zwart, Wilbert, Beltran, Himisha, Selth, Luke, Zoubeidi, Amina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Nature Publishing Group
• Subjects: 45/15; 45/22; 45/23; 45/91; 631/67/589/466; 631/67/68/2486; 692/699/67/1059/2326; 82/51; 96/106; 96/31; Androgen receptors; Androgens; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell fate; Cell Line, Tumor; Chromatin; Developmental Biology; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenetics; Gene Expression Regulation, Neoplastic - genetics; Gene Regulatory Networks - genetics; Gene Regulatory Networks - physiology; Homology; Humans; Life Sciences; Male; Neural stem cells; Phenotypes; Phosphorylation; Plastic properties; Plasticity; Polycomb group proteins; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - physiology; Stem Cells; Transcription; Tumors
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-021-00743-5

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks—granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes. Davies et al. demonstrate that androgen receptor–targeted therapy induces lineage-plastic transcriptional reprogramming, which is mediated by EZH2 and favours stem cell and neuronal gene networks in treatment-resistant prostate cancer.