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

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 GopalanDeyou Zheng, Mark A. Rubin, Howard I. Scher, Ping Chi, Yu Chen

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)792-806.e7
JournalCancer Cell
Volume32
Issue number6
DOIs
StatePublished - Dec 11 2017

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Keywords

  • ChIP-seq
  • HNF1A
  • HNF4G
  • SPINK1
  • androgen-deprivation therapy
  • castration resistance
  • enzalutamide
  • pioneer factor
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

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., ... Chen, Y. (2017). Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. Cancer Cell, 32(6), 792-806.e7. https://doi.org/10.1016/j.ccell.2017.10.008