Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Zeda Zhang; Chuanli Zhou; Xiaoling Li; Spencer D. Barnes; Su Deng; Elizabeth Hoover; Chi Chao Chen; Young Sun Lee; Yanxiao Zhang; Choushi Wang; Lauren A. Metang; Chao Wu; Carla Rodriguez Tirado; Nickolas A. Johnson; John Wongvipat; Kristina Navrazhina; Zhen Cao; Danielle Choi; Chun Hao Huang; Eliot Linton; Xiaoping Chen; Yupu Liang; Christopher E. Mason; Elisa de Stanchina; Wassim Abida; Amaia Lujambio; Sheng Li; Scott W. Lowe; Joshua T. Mendell; Venkat S. Malladi; Charles L. Sawyers; Ping Mu

doi:10.1016/j.ccell.2020.03.001

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

Zeda Zhang, Chuanli Zhou, Xiaoling Li, Spencer D. Barnes, Su Deng, Elizabeth Hoover, Chi Chao Chen, Young Sun Lee, Yanxiao Zhang, Choushi Wang, Lauren A. Metang, Chao Wu, Carla Rodriguez Tirado, Nickolas A. Johnson, John Wongvipat, Kristina Navrazhina, Zhen Cao, Danielle Choi, Chun Hao Huang, Eliot LintonXiaoping Chen, Yupu Liang, Christopher E. Mason, Elisa de Stanchina, Wassim Abida, Amaia Lujambio, Sheng Li, Scott W. Lowe, Joshua T. Mendell, Venkat S. Malladi, Charles L. Sawyers, Ping Mu

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Abstract

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

Original language	English
Pages (from-to)	584-598.e11
Journal	Cancer Cell
Volume	37
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2020.03.001
State	Published - 13 Apr 2020

Keywords

CHD1
NR2F1
NR3C1 (GR)
POU3F2 (BRN2)
TBX2
antiandrogen resistantce
castration-resistant prostate cancer
chromatin remodeling
lineage plasticity
tumor heterogeneity

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10.1016/j.ccell.2020.03.001

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Zhang, Z., Zhou, C., Li, X., Barnes, S. D., Deng, S., Hoover, E., Chen, C. C., Lee, Y. S., Zhang, Y., Wang, C., Metang, L. A., Wu, C., Tirado, C. R., Johnson, N. A., Wongvipat, J., Navrazhina, K., Cao, Z., Choi, D., Huang, C. H., ... Mu, P. (2020). Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell, 37(4), 584-598.e11. https://doi.org/10.1016/j.ccell.2020.03.001

@article{e785e95c92a64d15b7663939ec403f43,

title = "Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation",

abstract = "Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.",

keywords = "CHD1, NR2F1, NR3C1 (GR), POU3F2 (BRN2), TBX2, antiandrogen resistantce, castration-resistant prostate cancer, chromatin remodeling, lineage plasticity, tumor heterogeneity",

author = "Zeda Zhang and Chuanli Zhou and Xiaoling Li and Barnes, {Spencer D.} and Su Deng and Elizabeth Hoover and Chen, {Chi Chao} and Lee, {Young Sun} and Yanxiao Zhang and Choushi Wang and Metang, {Lauren A.} and Chao Wu and Tirado, {Carla Rodriguez} and Johnson, {Nickolas A.} and John Wongvipat and Kristina Navrazhina and Zhen Cao and Danielle Choi and Huang, {Chun Hao} and Eliot Linton and Xiaoping Chen and Yupu Liang and Mason, {Christopher E.} and {de Stanchina}, Elisa and Wassim Abida and Amaia Lujambio and Sheng Li and Lowe, {Scott W.} and Mendell, {Joshua T.} and Malladi, {Venkat S.} and Sawyers, {Charles L.} and Ping Mu",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = apr,

day = "13",

doi = "10.1016/j.ccell.2020.03.001",

language = "English",

volume = "37",

pages = "584--598.e11",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

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Zhang, Z, Zhou, C, Li, X, Barnes, SD, Deng, S, Hoover, E, Chen, CC, Lee, YS, Zhang, Y, Wang, C, Metang, LA, Wu, C, Tirado, CR, Johnson, NA, Wongvipat, J, Navrazhina, K, Cao, Z, Choi, D, Huang, CH, Linton, E, Chen, X, Liang, Y, Mason, CE, de Stanchina, E, Abida, W, Lujambio, A, Li, S, Lowe, SW, Mendell, JT, Malladi, VS, Sawyers, CL & Mu, P 2020, 'Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation', Cancer Cell, vol. 37, no. 4, pp. 584-598.e11. https://doi.org/10.1016/j.ccell.2020.03.001

TY - JOUR

T1 - Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

AU - Zhang, Zeda

AU - Zhou, Chuanli

AU - Li, Xiaoling

AU - Barnes, Spencer D.

AU - Deng, Su

AU - Hoover, Elizabeth

AU - Chen, Chi Chao

AU - Lee, Young Sun

AU - Zhang, Yanxiao

AU - Wang, Choushi

AU - Metang, Lauren A.

AU - Wu, Chao

AU - Tirado, Carla Rodriguez

AU - Johnson, Nickolas A.

AU - Wongvipat, John

AU - Navrazhina, Kristina

AU - Cao, Zhen

AU - Choi, Danielle

AU - Huang, Chun Hao

AU - Linton, Eliot

AU - Chen, Xiaoping

AU - Liang, Yupu

AU - Mason, Christopher E.

AU - de Stanchina, Elisa

AU - Abida, Wassim

AU - Lujambio, Amaia

AU - Li, Sheng

AU - Lowe, Scott W.

AU - Mendell, Joshua T.

AU - Malladi, Venkat S.

AU - Sawyers, Charles L.

AU - Mu, Ping

PY - 2020/4/13

Y1 - 2020/4/13

N2 - Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

AB - Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

KW - CHD1

KW - NR2F1

KW - NR3C1 (GR)

KW - POU3F2 (BRN2)

KW - TBX2

KW - antiandrogen resistantce

KW - castration-resistant prostate cancer

KW - chromatin remodeling

KW - lineage plasticity

KW - tumor heterogeneity

UR - http://www.scopus.com/inward/record.url?scp=85082959150&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.03.001

DO - 10.1016/j.ccell.2020.03.001

M3 - Article

C2 - 32220301

AN - SCOPUS:85082959150

SN - 1535-6108

VL - 37

SP - 584-598.e11

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

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