A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Yundong He; Ting Wei; Zhenqing Ye; Jacob J. Orme; Dong Lin; Haoyue Sheng; Ladan Fazli; R. Jeffrey Karnes; Rafael Jimenez; Liguo Wang; Liewei Wang; Martin E. Gleave; Yuzhuo Wang; Lei Shi; Haojie Huang

doi:10.1038/s41467-021-21860-7

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Yundong He
, Ting Wei
, Zhenqing Ye
, Jacob J. Orme
, Dong Lin
, Haoyue Sheng
, Ladan Fazli
, R. Jeffrey Karnes
, Rafael Jimenez
, Liguo Wang
, Liewei Wang
, Martin E. Gleave
, Yuzhuo Wang
, Lei Shi^*
, Haojie Huang^*

^*Corresponding author for this work

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

73 Scopus citations

Abstract

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

Original language	English
Article number	1521
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21860-7
State	Published - 1 Dec 2021
Externally published	Yes

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title = "A noncanonical AR addiction drives enzalutamide resistance in prostate cancer",

abstract = "Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.",

author = "Yundong He and Ting Wei and Zhenqing Ye and Orme, \{Jacob J.\} and Dong Lin and Haoyue Sheng and Ladan Fazli and \{Jeffrey Karnes\}, R. and Rafael Jimenez and Liguo Wang and Liewei Wang and Gleave, \{Martin E.\} and Yuzhuo Wang and Lei Shi and Haojie Huang",

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doi = "10.1038/s41467-021-21860-7",

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T1 - A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

AU - He, Yundong

AU - Wei, Ting

AU - Ye, Zhenqing

AU - Orme, Jacob J.

AU - Lin, Dong

AU - Sheng, Haoyue

AU - Fazli, Ladan

AU - Jeffrey Karnes, R.

AU - Jimenez, Rafael

AU - Wang, Liguo

AU - Wang, Liewei

AU - Gleave, Martin E.

AU - Wang, Yuzhuo

AU - Shi, Lei

AU - Huang, Haojie

PY - 2021/12/1

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N2 - Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

AB - Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

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JO - Nature Communications

JF - Nature Communications

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M1 - 1521

ER -

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Abstract

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