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 |
