An androgen receptor change underlies parentage infidelity in treatment-resistant prostate most cancers

This article was originally published here

Nat Cell Biol. 2021 Sept. 6, doi: 10.1038 / s41556-021-00743-5. Online before printing.


Cancers adapt to increasingly effective targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumors can escape the epithelial lineage and develop into a highly plastic state as an adaptive response to strong androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumors adopt alternative lineage identities, with changes in chromatin architecture directing AR transcription redirection. Zeste Homolog 2 (EZH2) epigenetic regulator enhancer occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neural gene networks, conferring privileges associated with both fates. This function of EZH2 was linked to the phosphorylation of T350 and the establishment of a non-canonical Polycomb sub-complex. Our study provides mechanistic insights into the plasticity of the lineage infidelity state controlled by AR reprogramming, which allowed us to redirect cell fate through the modulation of EZH2 and AR, demonstrating the clinical potential of reversing resistance phenotypes highlights.

PMID: 34489572 | DOI: 10.1038 / s41556-021-00743-5

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