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Cancer Cell. 2019 Apr 15;35(4):603-617.e8. doi: 10.1016/j.ccell.2019.03.001. Epub 2019 Mar 28.

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Author information

1
Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
2
Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
3
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
4
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
6
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
7
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
10
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
11
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
12
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
13
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
14
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
15
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
16
Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: chb9074@med.cornell.edu.

Abstract

Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression.

KEYWORDS:

AR; CHD1; HOXB13; androgen receptor; chromatin remodeling; cistrome reprogramming; epigenetics; interactome; prostate cancer; prostate cancer subclass

PMID:
30930119
PMCID:
PMC6467783
[Available on 2020-04-15]
DOI:
10.1016/j.ccell.2019.03.001

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