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

Shukla, Shipra; Cyrta, Joanna; Murphy, Devan A; Walczak, Edward G; Ran, Leili; Agrawal, Praveen; Xie, Yuanyuan; Chen, Yuedan; Wang, Shangqian; Zhan, Yu; Li, Dan; Wong, Elissa W P; Sboner, Andrea; Beltran, Himisha; Mosquera, Juan Miguel; Sher, Jessica; Cao, Zhen; Wongvipat, John; Koche, Richard P; Gopalan, Anuradha; ... (2017). Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. Cancer cell, 32(6), 792-806.e7. Cell Press 10.1016/j.ccell.2017.10.008

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

500 Science
500 Science > 570 Life sciences; biology

ISSN:

1535-6108

Publisher:

Cell Press

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

12 Feb 2018 09:30

Last Modified:

12 Feb 2018 09:30

Publisher DOI:

10.1016/j.ccell.2017.10.008

PubMed ID:

29153843

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.110729

URI:

https://boris.unibe.ch/id/eprint/110729

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