Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Zhong Chen; Dayong Wu; Jennifer M. Thomas-Ahner; Changxue Lu; Pei Zhao; Qingfu Zhang; Connor Geraghty; Pearlly S. Yan; William Hankey; Benjamin Sunkel; Xiaolong Cheng; Emmanuel S. Antonarakis; Qi En Wang; Zhihua Liu; Tim H.M. Huang; Victor X. Jin; Steven K. Clinton; Jun Luo; Jiaoti Huang; Qianben Wang

doi:10.1073/pnas.1718811115

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Zhong Chen
, Dayong Wu
, Jennifer M. Thomas-Ahner
, Changxue Lu
, Pei Zhao
, Qingfu Zhang
, Connor Geraghty
, Pearlly S. Yan
, William Hankey
, Benjamin Sunkel
, Xiaolong Cheng
, Emmanuel S. Antonarakis
, Qi En Wang
, Zhihua Liu
, Tim H.M. Huang
, Victor X. Jin
, Steven K. Clinton
, Jun Luo
, Jiaoti Huang
, Qianben Wang

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

130 Scopus citations

Abstract

The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.

Original language	English (US)
Pages (from-to)	6810-6815
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	26
DOIs	https://doi.org/10.1073/pnas.1718811115
State	Published - Jun 26 2018
Externally published	Yes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This work was supported by NIH Grants U54 CA217297 (to Q.W., V.X.J., and T.H.-M.H.), R01 GM120221 (to Q.W.), R01 CA200853 (to Q.W., J.H., and S.K.C.), R01 CA172603, R01 CA205001, and R01 CA212403 (to J.H.); Department of Defense Grant W81XWH-16-1-0291 (to Q.W., S.K.C., and J.H.); and the Prostate Cancer Foundation Joyce and Larry Stupski Prostate Cancer Precision Oncology Special Challenge Award (to J.H.).

Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.

Keywords

AR-V7
Castration-resistant prostate cancer
HoxB13
Motif-resolution cistromes

UN SDGs

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

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10.1073/pnas.1718811115

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Chen, Z., Wu, D., Thomas-Ahner, J. M., Lu, C., Zhao, P., Zhang, Q., Geraghty, C., Yan, P. S., Hankey, W., Sunkel, B., Cheng, X., Antonarakis, E. S., Wang, Q. E., Liu, Z., Huang, T. H. M., Jin, V. X., Clinton, S. K., Luo, J., Huang, J., & Wang, Q. (2018). Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proceedings of the National Academy of Sciences of the United States of America, 115(26), 6810-6815. https://doi.org/10.1073/pnas.1718811115

Chen, Z, Wu, D, Thomas-Ahner, JM, Lu, C, Zhao, P, Zhang, Q, Geraghty, C, Yan, PS, Hankey, W, Sunkel, B, Cheng, X, Antonarakis, ES, Wang, QE, Liu, Z, Huang, THM, Jin, VX, Clinton, SK, Luo, J, Huang, J & Wang, Q 2018, 'Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 26, pp. 6810-6815. https://doi.org/10.1073/pnas.1718811115

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title = "Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13",

abstract = "The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.",

keywords = "AR-V7, Castration-resistant prostate cancer, HoxB13, Motif-resolution cistromes",

author = "Zhong Chen and Dayong Wu and Thomas-Ahner, \{Jennifer M.\} and Changxue Lu and Pei Zhao and Qingfu Zhang and Connor Geraghty and Yan, \{Pearlly S.\} and William Hankey and Benjamin Sunkel and Xiaolong Cheng and Antonarakis, \{Emmanuel S.\} and Wang, \{Qi En\} and Zhihua Liu and Huang, \{Tim H.M.\} and Jin, \{Victor X.\} and Clinton, \{Steven K.\} and Jun Luo and Jiaoti Huang and Qianben Wang",

note = "Funding Information: ACKNOWLEDGMENTS. This work was supported by NIH Grants U54 CA217297 (to Q.W., V.X.J., and T.H.-M.H.), R01 GM120221 (to Q.W.), R01 CA200853 (to Q.W., J.H., and S.K.C.), R01 CA172603, R01 CA205001, and R01 CA212403 (to J.H.); Department of Defense Grant W81XWH-16-1-0291 (to Q.W., S.K.C., and J.H.); and the Prostate Cancer Foundation Joyce and Larry Stupski Prostate Cancer Precision Oncology Special Challenge Award (to J.H.). Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",

year = "2018",

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doi = "10.1073/pnas.1718811115",

language = "English (US)",

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T1 - Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

AU - Chen, Zhong

AU - Wu, Dayong

AU - Thomas-Ahner, Jennifer M.

AU - Lu, Changxue

AU - Zhao, Pei

AU - Zhang, Qingfu

AU - Geraghty, Connor

AU - Yan, Pearlly S.

AU - Hankey, William

AU - Sunkel, Benjamin

AU - Cheng, Xiaolong

AU - Antonarakis, Emmanuel S.

AU - Wang, Qi En

AU - Liu, Zhihua

AU - Huang, Tim H.M.

AU - Jin, Victor X.

AU - Clinton, Steven K.

AU - Luo, Jun

AU - Huang, Jiaoti

AU - Wang, Qianben

N1 - Funding Information: ACKNOWLEDGMENTS. This work was supported by NIH Grants U54 CA217297 (to Q.W., V.X.J., and T.H.-M.H.), R01 GM120221 (to Q.W.), R01 CA200853 (to Q.W., J.H., and S.K.C.), R01 CA172603, R01 CA205001, and R01 CA212403 (to J.H.); Department of Defense Grant W81XWH-16-1-0291 (to Q.W., S.K.C., and J.H.); and the Prostate Cancer Foundation Joyce and Larry Stupski Prostate Cancer Precision Oncology Special Challenge Award (to J.H.). Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.

PY - 2018/6/26

Y1 - 2018/6/26

N2 - The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.

AB - The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.

KW - AR-V7

KW - Castration-resistant prostate cancer

KW - HoxB13

KW - Motif-resolution cistromes

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UR - https://www.scopus.com/pages/publications/85049003766#tab=citedBy

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AN - SCOPUS:85049003766

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Abstract

Bibliographical note

Keywords

UN SDGs

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