Open AccessAn androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer
Author(s) -
Alastair Davies,
Shaghayegh Nouruzi,
Dwaipayan Ganguli,
Takeshi Namekawa,
Daksh Thaper,
Simon Linder,
Fatih Karaoğlanoğlu,
Meltem E. Omur,
Soojin Kim,
Maxim Kobelev,
Sahil Kumar,
Olena Sivak,
Chiara Bostock,
Jennifer Bishop,
Marlous Hoogstraat,
Amina Talal,
Suzan Stelloo,
Henk van der Poel,
Andries M. Bergman,
Musaddeque Ahmed,
Ladan Fazli,
Haojie Huang,
Wayne D. Tilley,
David W. Goodrich,
Felix Y. Feng,
Martin Gleave,
Housheng Hansen He,
Faraz Hach,
Wilbert Zwart,
Himisha Beltran,
Luke A. Selth,
Amina Zoubeidi
Publication year - 2021
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-021-00743-5
Subject(s) - reprogramming , ezh2 , biology , prc2 , epigenetics , chromatin , enhancer , lineage (genetic) , phenotype , androgen receptor , regulator , cancer research , prostate cancer , microbiology and biotechnology , genetics , cancer , cell , gene , transcription factor
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.