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 Gopalan; Deyou Zheng; Mark A. Rubin; Howard I. Scher; Ping Chi; Yu Chen

doi:10.1016/j.ccell.2017.10.008

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

Neurology

Research output: Contribution to journal › Article › peer-review

49 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 language	English (US)
Pages (from-to)	792-806.e7
Journal	Cancer Cell
Volume	32
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.10.008
State	Published - Dec 11 2017

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2017.10.008

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

Shukla, 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, JM, Sher, J, Cao, Z, Wongvipat, J, Koche, RP, Gopalan, A, Zheng, D, Rubin, MA, Scher, HI, Chi, P & Chen, Y 2017, 'Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance', Cancer Cell, vol. 32, no. 6, pp. 792-806.e7. https://doi.org/10.1016/j.ccell.2017.10.008

@article{9811ae4ad539453eb21c01c567fe048d,

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.",

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

author = "Shipra Shukla and Joanna Cyrta and Murphy, {Devan A.} and Walczak, {Edward G.} and Leili Ran and Praveen Agrawal and Yuanyuan Xie and Yuedan Chen and Shangqian Wang and Yu Zhan and Dan Li and Wong, {Elissa W.P.} and Andrea Sboner and Himisha Beltran and Mosquera, {Juan Miguel} and Jessica Sher and Zhen Cao and John Wongvipat and Koche, {Richard P.} and Anuradha Gopalan and Deyou Zheng and Rubin, {Mark A.} and Scher, {Howard I.} and Ping Chi and Yu Chen",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = dec,

day = "11",

doi = "10.1016/j.ccell.2017.10.008",

language = "English (US)",

volume = "32",

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T1 - Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance

AU - Shukla, Shipra

AU - Cyrta, Joanna

AU - Murphy, Devan A.

AU - Walczak, Edward G.

AU - Ran, Leili

AU - Agrawal, Praveen

AU - Xie, Yuanyuan

AU - Chen, Yuedan

AU - Wang, Shangqian

AU - Zhan, Yu

AU - Li, Dan

AU - Wong, Elissa W.P.

AU - Sboner, Andrea

AU - Beltran, Himisha

AU - Mosquera, Juan Miguel

AU - Sher, Jessica

AU - Cao, Zhen

AU - Wongvipat, John

AU - Koche, Richard P.

AU - Gopalan, Anuradha

AU - Zheng, Deyou

AU - Rubin, Mark A.

AU - Scher, Howard I.

AU - Chi, Ping

AU - Chen, Yu

PY - 2017/12/11

Y1 - 2017/12/11

N2 - 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.

AB - 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.

KW - ChIP-seq

KW - HNF1A

KW - HNF4G

KW - SPINK1

KW - androgen-deprivation therapy

KW - castration resistance

KW - enzalutamide

KW - pioneer factor

KW - prostate cancer

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U2 - 10.1016/j.ccell.2017.10.008

DO - 10.1016/j.ccell.2017.10.008

M3 - Article

C2 - 29153843

AN - SCOPUS:85034415477

SN - 1535-6108

VL - 32

SP - 792-806.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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