An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer
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 recepto...
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| Veröffentlicht in: | Nature cell biology 2021-09, Vol.23 (9), p.1023-1034 |
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| creator | Davies, Alastair Nouruzi, Shaghayegh Ganguli, Dwaipayan Namekawa, Takeshi Thaper, Daksh Linder, Simon Karaoğlanoğlu, Fatih Omur, Meltem E. Kim, Soojin Kobelev, Maxim Kumar, Sahil Sivak, Olena Bostock, Chiara Bishop, Jennifer Hoogstraat, Marlous Talal, Amina Stelloo, Suzan van der Poel, Henk Bergman, Andries M. Ahmed, Musaddeque Fazli, Ladan Huang, Haojie Tilley, Wayne Goodrich, David Feng, Felix Y. Gleave, Martin He, Housheng Hansen Hach, Faraz Zwart, Wilbert Beltran, Himisha Selth, Luke Zoubeidi, Amina |
| description | 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.
Davies et al. demonstrate that androgen receptor–targeted therapy induces lineage-plastic transcriptional reprogramming, which is mediated by EZH2 and favours stem cell and neuronal gene networks in treatment-resistant prostate cancer. |
| doi_str_mv | 10.1038/s41556-021-00743-5 |
| format | Article |
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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.
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Jennifer</au><au>Hoogstraat, Marlous</au><au>Talal, Amina</au><au>Stelloo, Suzan</au><au>van der Poel, Henk</au><au>Bergman, Andries M.</au><au>Ahmed, Musaddeque</au><au>Fazli, Ladan</au><au>Huang, Haojie</au><au>Tilley, Wayne</au><au>Goodrich, David</au><au>Feng, Felix Y.</au><au>Gleave, Martin</au><au>He, Housheng Hansen</au><au>Hach, Faraz</au><au>Zwart, Wilbert</au><au>Beltran, Himisha</au><au>Selth, Luke</au><au>Zoubeidi, Amina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2021-09-01</date><risdate>2021</risdate><volume>23</volume><issue>9</issue><spage>1023</spage><epage>1034</epage><pages>1023-1034</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><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.
Davies et al. demonstrate that androgen receptor–targeted therapy induces lineage-plastic transcriptional reprogramming, which is mediated by EZH2 and favours stem cell and neuronal gene networks in treatment-resistant prostate cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34489572</pmid><doi>10.1038/s41556-021-00743-5</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-0963-7687</orcidid><orcidid>https://orcid.org/0000-0003-2751-6413</orcidid><orcidid>https://orcid.org/0000-0003-1893-2626</orcidid><orcidid>https://orcid.org/0000-0002-0498-142X</orcidid><orcidid>https://orcid.org/0000-0003-3259-2226</orcidid><orcidid>https://orcid.org/0000-0001-5223-2549</orcidid><orcidid>https://orcid.org/0000-0002-2236-920X</orcidid><orcidid>https://orcid.org/0000-0002-4916-1177</orcidid><orcidid>https://orcid.org/0000-0002-9823-7289</orcidid><orcidid>https://orcid.org/0000-0002-4686-1418</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-7392 |
| ispartof | Nature cell biology, 2021-09, Vol.23 (9), p.1023-1034 |
| issn | 1465-7392 1476-4679 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9012003 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 45/15 45/22 45/23 45/91 631/67/589/466 631/67/68/2486 692/699/67/1059/2326 82/51 96/106 96/31 Androgen receptors Androgens Biomedical and Life Sciences Cancer Research Cell Biology Cell fate Cell Line, Tumor Chromatin Developmental Biology Enhancer of Zeste Homolog 2 Protein - genetics Enhancer of Zeste Homolog 2 Protein - metabolism Epigenetics Gene Expression Regulation, Neoplastic - genetics Gene Regulatory Networks - genetics Gene Regulatory Networks - physiology Homology Humans Life Sciences Male Neural stem cells Phenotypes Phosphorylation Plastic properties Plasticity Polycomb group proteins Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Receptors Receptors, Androgen - genetics Receptors, Androgen - metabolism Signal Transduction - physiology Stem Cells Transcription Tumors |
| title | An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T10%3A40%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20androgen%20receptor%20switch%20underlies%20lineage%20infidelity%20in%20treatment-resistant%20prostate%20cancer&rft.jtitle=Nature%20cell%20biology&rft.au=Davies,%20Alastair&rft.date=2021-09-01&rft.volume=23&rft.issue=9&rft.spage=1023&rft.epage=1034&rft.pages=1023-1034&rft.issn=1465-7392&rft.eissn=1476-4679&rft_id=info:doi/10.1038/s41556-021-00743-5&rft_dat=%3Cproquest_pubme%3E2572072252%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2572072252&rft_id=info:pmid/34489572&rfr_iscdi=true |