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

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.
Authors	Shipra Shukla, Joanna Cyrta, Devan A Murphy, Edward G Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Dan Li, Elissa W P Wong, Andrea Sboner, Himisha Beltran, Juan Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P Koche, Anuradha Gopalan, Deyou Zheng, Mark A Rubin, Howard I Scher, Ping Chi, Yu Chen
Journal	Cancer cell (Cancer Cell) Vol. 32 Issue 6 Pg. 792-806.e7 (Dec 11 2017) ISSN: 1878-3686 [Electronic] United States
PMID	29153843 (Publication Type: Journal Article)
Copyright	Copyright © 2017 Elsevier Inc. All rights reserved.
Chemical References	HNF1A protein, human HNF4G protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 SPINK1 protein, human Trypsin Inhibitor, Kazal Pancreatic
Topics	Animals Drug Resistance, Neoplasm (physiology) Gene Expression Regulation, Neoplastic (physiology) Hepatocyte Nuclear Factor 1-alpha (metabolism) Hepatocyte Nuclear Factor 4 (metabolism) Heterografts Humans Male Mice Mice, SCID Prostatic Neoplasms, Castration-Resistant (metabolism, pathology) Trypsin Inhibitor, Kazal Pancreatic (biosynthesis)

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