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 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 Tilley; David Goodrich; Felix Y. Feng; Martin Gleave; Housheng Hansen He; Faraz Hach; Wilbert Zwart; Himisha Beltran; Luke Selth; Amina Zoubeidi

doi:10.1038/s41556-021-00743-5

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 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 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

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	1023-1034
Number of pages	12
Journal	Nature Cell Biology
Volume	23
Issue number	9
DOIs	https://doi.org/10.1038/s41556-021-00743-5
State	Published - Sep 2021

ASJC Scopus subject areas

Cell Biology

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Davies, A., Nouruzi, S., Ganguli, D., Namekawa, T., Thaper, D., Linder, S., Karaoğlanoğlu, F., Omur, M. E., Kim, S., Kobelev, M., Kumar, S., Sivak, O., Bostock, C., Bishop, J., Hoogstraat, M., Talal, A., Stelloo, S., van der Poel, H., Bergman, A. M., ... Zoubeidi, A. (2021). An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer. Nature Cell Biology, 23(9), 1023-1034. https://doi.org/10.1038/s41556-021-00743-5

Davies, A, Nouruzi, S, Ganguli, D, Namekawa, T, Thaper, D, Linder, S, Karaoğlanoğlu, F, Omur, ME, Kim, S, Kobelev, M, Kumar, S, Sivak, O, Bostock, C, Bishop, J, Hoogstraat, M, Talal, A, Stelloo, S, van der Poel, H, Bergman, AM, Ahmed, M, Fazli, L, Huang, H, Tilley, W, Goodrich, D, Feng, FY, Gleave, M, He, HH, Hach, F, Zwart, W, Beltran, H, Selth, L & Zoubeidi, A 2021, 'An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer', Nature Cell Biology, vol. 23, no. 9, pp. 1023-1034. https://doi.org/10.1038/s41556-021-00743-5

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title = "An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer",

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.",

author = "Alastair Davies and Shaghayegh Nouruzi and Dwaipayan Ganguli and Takeshi Namekawa and Daksh Thaper and Simon Linder and Fatih Karaoğlanoğlu and Omur, {Meltem E.} and Soojin Kim and Maxim Kobelev and Sahil Kumar and Olena Sivak and Chiara Bostock and Jennifer Bishop and Marlous Hoogstraat and Amina Talal and Suzan Stelloo and {van der Poel}, Henk and Bergman, {Andries M.} and Musaddeque Ahmed and Ladan Fazli and Haojie Huang and Wayne Tilley and David Goodrich and Feng, {Felix Y.} and Martin Gleave and He, {Housheng Hansen} and Faraz Hach and Wilbert Zwart and Himisha Beltran and Luke Selth and Amina Zoubeidi",

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AU - Nouruzi, Shaghayegh

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AU - Namekawa, Takeshi

AU - Thaper, Daksh

AU - Linder, Simon

AU - Karaoğlanoğlu, Fatih

AU - Omur, Meltem E.

AU - Kim, Soojin

AU - Kobelev, Maxim

AU - Kumar, Sahil

AU - Sivak, Olena

AU - Bostock, Chiara

AU - Bishop, Jennifer

AU - Hoogstraat, Marlous

AU - Talal, Amina

AU - Stelloo, Suzan

AU - van der Poel, Henk

AU - Bergman, Andries M.

AU - Ahmed, Musaddeque

AU - Fazli, Ladan

AU - Huang, Haojie

AU - Tilley, Wayne

AU - Goodrich, David

AU - Feng, Felix Y.

AU - Gleave, Martin

AU - He, Housheng Hansen

AU - Hach, Faraz

AU - Zwart, Wilbert

AU - Beltran, Himisha

AU - Selth, Luke

AU - Zoubeidi, Amina

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

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