Beltran Lab

You are here

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

TitleAberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.
Publication TypeJournal Article
Year of Publication2017
AuthorsShukla S, Cyrta J, Murphy DA, Walczak EG, Ran L, Agrawal P, Xie Y, Chen Y, Wang S, Zhan Y, Li D, Wong EWP, Sboner A, Beltran H, Mosquera JMiguel, Sher J, Cao Z, Wongvipat J, Koche RP, Gopalan A, Zheng D, Rubin MA, Scher HI, Chi P, Chen Y
JournalCancer Cell
Volume32
Issue6
Pagination792-806.e7
Date Published2017 Dec 11
ISSN1878-3686
KeywordsAnimals, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 4, Heterografts, Humans, Male, Mice, Mice, SCID, Prostatic Neoplasms, Castration-Resistant, Trypsin Inhibitor, Kazal Pancreatic
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.

DOI10.1016/j.ccell.2017.10.008
Alternate JournalCancer Cell
PubMed ID29153843
PubMed Central IDPMC5728174
Grant ListR01 CA193837 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08 CA140946 / CA / NCI NIH HHS / United States
R01 CA208100 / CA / NCI NIH HHS / United States
DP2 CA174499 / CA / NCI NIH HHS / United States
K08 CA151660 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
P50 CA140146 / CA / NCI NIH HHS / United States