[PDF][PDF] Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance

S Shukla, J Cyrta, DA Murphy, EG Walczak, L Ran… - Cancer cell, 2017 - cell.com
S Shukla, J Cyrta, DA Murphy, EG Walczak, L Ran, P Agrawal, Y Xie, Y Chen, S Wang
Cancer cell, 2017cell.com
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 …
Summary
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.
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