Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance Journal Article


Authors: Shukla, S.; Cyrta, J.; Murphy, D. A.; Walczak, E. G.; Ran, L.; Agrawal, P.; Xie, Y.; Chen, Y.; Wang, S.; Zhan, Y.; Li, D.; Wong, E. W. P.; Sboner, A.; Beltran, H.; Mosquera, J. M.; Sher, J.; Cao, Z.; Wongvipat, J.; Koche, R. P.; Gopalan, A.; Zheng, D.; Rubin, M. A.; Scher, H. I.; Chi, P.; Chen, Y.
Article 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. © 2017 Elsevier Inc.
Keywords: signal transduction; clinical article; controlled study; human tissue; unclassified drug; human cell; androgen; nonhuman; binding affinity; aprotinin; mouse; animal; metabolism; animals; mice; animal tissue; hepatocyte nuclear factor 3alpha; gene expression; gene expression profiling; protein protein interaction; transcription initiation; animal experiment; animal model; protein; protein binding; transcription factor; drug resistance; pathology; drug resistance, neoplasm; mice, scid; transcriptomics; tumor marker; physiology; carcinogenesis; cancer resistance; cancer hormone therapy; prostate cancer; gene expression regulation; gene expression regulation, neoplastic; biosynthesis; albumin; transcription regulation; xenograft; messenger rna; chromatin; nucleotide sequence; serine proteinase inhibitor; membrane protein; binding site; androgen receptor; down regulation; upregulation; glyceraldehyde 3 phosphate dehydrogenase; castration; gastrointestinal tract; androgen deprivation therapy; transcriptome; scid mouse; prealbumin; castration resistant prostate cancer; mucin; enhancer region; androgen-deprivation therapy; hepatocyte nuclear factor; complement component c5; tumor ablation; peptides and proteins; chip-seq; trypsin inhibitor, kazal pancreatic; castration resistance; blood clotting factor 5; enzalutamide; akr1c3 protein; humans; human; male; priority journal; article; prostatic neoplasms, castration-resistant; lncap cell line; heterografts; vitamin d binding protein; hepatocyte nuclear factor 4; hnf1a; hnf4g; pioneer factor; spink1; clrn3 protein; growth arrest specific protein 2; hepatocyte nuclear factor 1alpha; hepatocyte nuclear factor 4 gamma; mucin 13; nuclear receptor subfamily 1 group h member 4; tmed6 protein; ugt2b15 protein; hnf1a protein, human; hnf4g protein, human; spink1 protein, human; 22rv1 cell line; hepatocyte nuclear factor 1-alpha
Journal Title: Cancer Cell
Volume: 32
Issue: 6
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2017-12-11
Start Page: 792
End Page: 806.e7
Language: English
DOI: 10.1016/j.ccell.2017.10.008
PUBMED: 29153843
PROVIDER: scopus
PMCID: PMC5728174
DOI/URL:
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Yu Chen
    68 Chen
  2. Ping Chi
    47 Chi
  3. Anuradha Gopalan
    275 Gopalan
  4. Howard Scher
    835 Scher
  5. Leili Ran
    17 Ran
  6. Zhen Cao
    15 Cao
  7. Yuanyuan Xie
    8 Xie
  8. Shipra Shukla
    11 Shukla
  9. Wai Pung Elissa Wong
    12 Wong
  10. Richard Patrick Koche
    52 Koche
  11. Devan Anne Murphy
    11 Murphy
  12. Yuedan   Chen
    4 Chen
  13. Jessica   Sher
    10 Sher
  14. Yu   Zhan
    5 Zhan
  15. Shangqian   Wang
    13 Wang