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

被引：100

作者：

Davies, Alastair ^{[1
,2
]}

Nouruzi, Shaghayegh ^{[1
,2
]}

Ganguli, Dwaipayan ^{[2
]}

Namekawa, Takeshi ^{[2
]}

Thaper, Daksh ^{[1
,2
]}

Linder, Simon ^{[3
]}

Karaoglanoglu, Fatih ^{[2
,4
]}

Omur, Meltem E. ^{[1
,2
]}

Kim, Soojin ^{[2
]}

Kobelev, Maxim ^{[1
,2
]}

Kumar, Sahil ^{[2
]}

Sivak, Olena ^{[2
]}

Bostock, Chiara ^{[2
]}

Bishop, Jennifer ^{[2
]}

Hoogstraat, Marlous ^{[3
]}

Talal, Amina ^{[2
]}

Stelloo, Suzan ^{[3
]}

van der Poel, Henk ^{[3
]}

Bergman, Andries M. ^{[3
]}

Ahmed, Musaddeque ^{[5
,6
]}

Fazli, Ladan ^{[2
]}

Huang, Haojie ^{[7
]}

Tilley, Wayne ^{[8
]}

Goodrich, David ^{[9
]}

Feng, Felix Y. ^{[10
]}

Gleave, Martin ^{[1
,2
]}

He, Housheng Hansen ^{[5
,6
]}

Hach, Faraz ^{[1
,2
,4
]}

Zwart, Wilbert ^{[3
]}

Beltran, Himisha ^{[11
]}

Selth, Luke ^{[8
,12
,13
,14
]}

Zoubeidi, Amina ^{[1
,2
]}

机构：

[1] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada

[2] Vancouver Prostate Ctr, Vancouver, BC, Canada

[3] Netherlands Canc Inst, Oncode Inst, Amsterdam, Netherlands

[4] Simon Fraser Univ, Sch Comp Sci, Burnaby, BC, Canada

[5] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[6] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[7] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA

[8] Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, SA, Australia

[9] Roswell Park Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY USA

[10] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA

[11] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[12] Univ Adelaide, Adelaide Med Sch, Dame Roma Mitchell Canc Res Labs, Adelaide, SA, Australia

[13] Univ Adelaide, Adelaide Med Sch, Freemasons Ctr Male Hlth & Wellbeing, Adelaide, SA, Australia

[14] Flinders Univ S Australia, Flinders Hlth & Med Res Inst, Coll Med & Publ Hlth, Bedford Pk, SA, Australia

来源：

NATURE CELL BIOLOGY | 2021年 / 23卷 / 09期

基金：

加拿大健康研究院;

关键词：

CASTRATION-RESISTANT; PHOSPHORYLATION; EZH2; PLASTICITY; ANTIANDROGEN; SIGNATURE; CHROMATIN; POLYCOMB; VARIANT; GENE;

D O I：

10.1038/s41556-021-00743-5

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1023 / +

页数：33

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