ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Ling Cai, Yi Hsuan Tsai, Ping Wang, Jun Wang, Dongxu Li, Huitao Fan, Yilin Zhao, Rohan Bareja, Rui Lu, Elizabeth M. Wilson, Andrea Sboner, Young E. Whang, Deyou Zheng, Joel S. Parker, H. Shelton Earp, Gang Greg Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer.

Original languageEnglish (US)
Pages (from-to)341-354.e6
JournalMolecular Cell
Volume72
Issue number2
DOIs
StatePublished - Oct 18 2018

Fingerprint

Androgen Receptors
Prostatic Neoplasms
Androgens
Castration
Therapeutics

Keywords

  • androgen receptor
  • AR-V7
  • BRD4
  • bromodomain inhibitor
  • castration resistance
  • Enzalutamide
  • MDV3100
  • prostate cancer
  • therapy resistance
  • ZFX

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. / Cai, Ling; Tsai, Yi Hsuan; Wang, Ping; Wang, Jun; Li, Dongxu; Fan, Huitao; Zhao, Yilin; Bareja, Rohan; Lu, Rui; Wilson, Elizabeth M.; Sboner, Andrea; Whang, Young E.; Zheng, Deyou; Parker, Joel S.; Earp, H. Shelton; Wang, Gang Greg.

In: Molecular Cell, Vol. 72, No. 2, 18.10.2018, p. 341-354.e6.

Research output: Contribution to journalArticle

Cai, L, Tsai, YH, Wang, P, Wang, J, Li, D, Fan, H, Zhao, Y, Bareja, R, Lu, R, Wilson, EM, Sboner, A, Whang, YE, Zheng, D, Parker, JS, Earp, HS & Wang, GG 2018, 'ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer', Molecular Cell, vol. 72, no. 2, pp. 341-354.e6. https://doi.org/10.1016/j.molcel.2018.08.029
Cai, Ling ; Tsai, Yi Hsuan ; Wang, Ping ; Wang, Jun ; Li, Dongxu ; Fan, Huitao ; Zhao, Yilin ; Bareja, Rohan ; Lu, Rui ; Wilson, Elizabeth M. ; Sboner, Andrea ; Whang, Young E. ; Zheng, Deyou ; Parker, Joel S. ; Earp, H. Shelton ; Wang, Gang Greg. / ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. In: Molecular Cell. 2018 ; Vol. 72, No. 2. pp. 341-354.e6.
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abstract = "Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer.",
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AU - Cai, Ling

AU - Tsai, Yi Hsuan

AU - Wang, Ping

AU - Wang, Jun

AU - Li, Dongxu

AU - Fan, Huitao

AU - Zhao, Yilin

AU - Bareja, Rohan

AU - Lu, Rui

AU - Wilson, Elizabeth M.

AU - Sboner, Andrea

AU - Whang, Young E.

AU - Zheng, Deyou

AU - Parker, Joel S.

AU - Earp, H. Shelton

AU - Wang, Gang Greg

PY - 2018/10/18

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N2 - Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer.

AB - Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer.

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KW - therapy resistance

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