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

Research output: Contribution to journal › Article

1 Scopus citations

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 (US)
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 - Apr 13 2020

Keywords

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

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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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

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. / Zhang, Zeda; Zhou, Chuanli; Li, Xiaoling; Barnes, Spencer D.; Deng, Su; Hoover, Elizabeth; Chen, Chi Chao; Lee, Young Sun; Zhang, Yanxiao; Wang, Choushi; Metang, Lauren A.; Wu, Chao; Tirado, Carla Rodriguez; Johnson, Nickolas A.; Wongvipat, John; Navrazhina, Kristina; Cao, Zhen; Choi, Danielle; Huang, Chun Hao; Linton, Eliot; Chen, Xiaoping; Liang, Yupu; Mason, Christopher E.; de Stanchina, Elisa; Abida, Wassim; Lujambio, Amaia; Li, Sheng; Lowe, Scott W.; Mendell, Joshua T.; Malladi, Venkat S.; Sawyers, Charles L.; Mu, Ping.

In: Cancer Cell, Vol. 37, No. 4, 13.04.2020, p. 584-598.e11.

Research output: Contribution to journal › Article

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

Zhang, Zeda ; Zhou, Chuanli ; Li, Xiaoling ; Barnes, Spencer D. ; Deng, Su ; Hoover, Elizabeth ; Chen, Chi Chao ; Lee, Young Sun ; Zhang, Yanxiao ; Wang, Choushi ; Metang, Lauren A. ; Wu, Chao ; Tirado, Carla Rodriguez ; Johnson, Nickolas A. ; Wongvipat, John ; Navrazhina, Kristina ; Cao, Zhen ; Choi, Danielle ; Huang, Chun Hao ; Linton, Eliot ; Chen, Xiaoping ; Liang, Yupu ; Mason, Christopher E. ; de Stanchina, Elisa ; Abida, Wassim ; Lujambio, Amaia ; Li, Sheng ; Lowe, Scott W. ; Mendell, Joshua T. ; Malladi, Venkat S. ; Sawyers, Charles L. ; Mu, Ping. / Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. In: Cancer Cell. 2020 ; Vol. 37, No. 4. pp. 584-598.e11.

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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.",

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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

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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.

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KW - POU3F2 (BRN2)

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