@article{9811ae4ad539453eb21c01c567fe048d,
title = "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. Shukla et al. identify an aberrantly expressed gastrointestinal-lineage transcriptome governed by HNF4G and HNF1A in ∼30% of castration-resistant prostate cancer. HNF4G is a pioneer factor for this transcriptional program and its ectopic expression at physiologic levels reduces sensitivity to hormone deprivation.",
keywords = "ChIP-seq, HNF1A, HNF4G, SPINK1, androgen-deprivation therapy, castration resistance, enzalutamide, pioneer factor, prostate cancer",
author = "Shipra Shukla and Joanna Cyrta and Murphy, {Devan A.} and Walczak, {Edward G.} and Leili Ran and Praveen Agrawal and Yuanyuan Xie and Yuedan Chen and Shangqian Wang and Yu Zhan and Dan Li and Wong, {Elissa W.P.} and Andrea Sboner and Himisha Beltran and Mosquera, {Juan Miguel} and Jessica Sher and Zhen Cao and John Wongvipat and Koche, {Richard P.} and Anuradha Gopalan and Deyou Zheng and Rubin, {Mark A.} and Scher, {Howard I.} and Ping Chi and Yu Chen",
note = "Funding Information: We would like to thank Dr. Ling Cai and Daniel Neil Weinberg for reagent development, and Dr. Takao Hamakubo for HNF4G antibody. Next-generation sequencing and gene expression arrays were done at the Memorial Sloan Kettering Cancer Center (MSKCC) Genomics Core Facility (for ChIP-seq and RNA-seq) and New York Genome Center (for ATAC-seq). ATAC-seq was performed by the Epigenomics Core at MSKCC. Immunohistochemistry was performed at the Translational Research Program facility, Department of Pathology and Laboratory Medicine at Weill Cornell Medicine. We would like to thank support and feedback from the Prostate Cancer Foundation. This work was supported by grants from the NCI (K08CA140946, Y.C.; R01 CA208100, Y.C.; R01CA193837, Y.C.; P50CA092629, Y.C., H.I.S., and A.G.; P30CA008748, P.C., Y.C., and H.I.S.; P50CA140146, P.C.; K08CA151660, P.C.; DP2 CA174499, P.C.; U01 CA111275-09, M.A.R. and J.M.M.); US DOD (W81XWH-10-1-0197) and Starr Cancer Consortium, Y.C., P.C., G.S., and M.A.R.; Geoffrey Beene Cancer Research Center, Y.C. and P.C.; Gerstner Family Foundation, Y.C.; Bressler Scholars Fund, Y.C.; GIST Cancer Research Fund, P.C.; Shuman Fund, P.C.; and GIST Cancer Awareness Fund, P.C. J.C. was supported by the Nuovo-Soldati foundation. Funding Information: We would like to thank Dr. Ling Cai and Daniel Neil Weinberg for reagent development, and Dr. Takao Hamakubo for HNF4G antibody. Next-generation sequencing and gene expression arrays were done at the Memorial Sloan Kettering Cancer Center (MSKCC) Genomics Core Facility (for ChIP-seq and RNA-seq) and New York Genome Center (for ATAC-seq). ATAC-seq was performed by the Epigenomics Core at MSKCC. Immunohistochemistry was performed at the Translational Research Program facility, Department of Pathology and Laboratory Medicine at Weill Cornell Medicine. We would like to thank support and feedback from the Prostate Cancer Foundation . This work was supported by grants from the NCI ( K08CA140946 , Y.C.; R01 CA208100 , Y.C.; R01CA193837 , Y.C.; P50CA092629 , Y.C., H.I.S., and A.G.; P30CA008748 , P.C., Y.C., and H.I.S.; P50CA140146 , P.C.; K08CA151660 , P.C.; DP2 CA174499 , P.C.; U01 CA111275-09 , M.A.R. and J.M.M.); US DOD ( W81XWH-10-1-0197 ) and Starr Cancer Consortium , Y.C., P.C., G.S., and M.A.R.; Geoffrey Beene Cancer Research Center , Y.C. and P.C.; Gerstner Family Foundation , Y.C.; Bressler Scholars Fund , Y.C.; GIST Cancer Research Fund , P.C.; Shuman Fund , P.C.; and GIST Cancer Awareness Fund , P.C. J.C. was supported by the Nuovo-Soldati foundation . Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "11",
doi = "10.1016/j.ccell.2017.10.008",
language = "English (US)",
volume = "32",
pages = "792--806.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}
