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

Alastair Davies, Shaghayegh Nouruzi, Dwaipayan Ganguli, Takeshi Namekawa, Daksh Thaper, Simon Linder, Fatih Karaoglanoglu, 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 AhmedLadan Fazli, Haojie Huang, Wayne Tilley, David Goodrich, Felix Y. Feng, Martin Gleave, Housheng Hansen He, Faraz Hach, Wilbert Zwart, Himisha Beltran, Luke Selth, Amina Zoubeidi

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1023-1034
Number of pages12
JournalNature Cell Biology
Volume23
Issue number9
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Cancer epigenetics
  • Cancer therapeutic resistance
  • Prostate cancer

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