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Cancer Cell. 2017 Dec 11;32(6):792-806.e7. doi: 10.1016/j.ccell.2017.10.008. Epub 2017 Nov 16.

Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA.
3
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
4
Yale School of Medicine, New Haven, CT 06511, USA.
5
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Medical College, New York, NY 10065, USA.
6
Englander Institute for Precision Medicine of Weill Cornell Medicine and New York-Presbyterian, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
7
Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Departments of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chip@mskcc.org.
12
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: cheny1@mskcc.org.

Abstract

Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.

KEYWORDS:

ChIP-seq; HNF1A; HNF4G; SPINK1; androgen-deprivation therapy; castration resistance; enzalutamide; pioneer factor; prostate cancer

PMID:
29153843
PMCID:
PMC5728174
DOI:
10.1016/j.ccell.2017.10.008
[Indexed for MEDLINE]
Free PMC Article

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