| Literature DB >> 34489572 |
Alastair Davies1,2, Shaghayegh Nouruzi1,2, Dwaipayan Ganguli2, Takeshi Namekawa2, Daksh Thaper1,2, Simon Linder3, Fatih Karaoğlanoğlu2,4, Meltem E Omur1,2, Soojin Kim2, Maxim Kobelev1,2, Sahil Kumar2, Olena Sivak2, Chiara Bostock2, Jennifer Bishop2, Marlous Hoogstraat3, Amina Talal2, Suzan Stelloo3, Henk van der Poel3, Andries M Bergman3, Musaddeque Ahmed5,6, Ladan Fazli2, Haojie Huang7, Wayne Tilley8, David Goodrich9, Felix Y Feng10, Martin Gleave1,2, Housheng Hansen He5,6, Faraz Hach2,4, Wilbert Zwart3, Himisha Beltran11, Luke Selth8,12,13, Amina Zoubeidi14,15.
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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34489572 PMCID： PMC9012003 DOI： 10.1038/s41556-021-00743-5
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.213