An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

Jindan Yu; Jianjun Yu; Ram Shankar Mani; Qi Cao; Chad J. Brenner; Xuhong Cao; Xiaoju Wang; Longtao Wu; James Li; Ming Hu; Yusong Gong; Hong Cheng; Bharathi Laxman; Adaikkalam Vellaichamy; Sunita Shankar; Yong Li; Saravana M. Dhanasekaran; Roger Morey; Terrence Barrette; Robert J. Lonigro; Scott A. Tomlins; Sooryanarayana Varambally; Zhaohui S. Qin; Arul M. Chinnaiyan

doi:10.1016/j.ccr.2010.03.018

An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

Jindan Yu, Jianjun Yu, Ram Shankar Mani, Qi Cao, Chad J. Brenner, Xuhong Cao, Xiaoju Wang, Longtao Wu, James Li, Ming Hu, Yusong Gong, Hong Cheng, Bharathi Laxman, Adaikkalam Vellaichamy, Sunita Shankar, Yong Li, Saravana M. Dhanasekaran, Roger Morey, Terrence Barrette, Robert J. LonigroScott A. Tomlins, Sooryanarayana Varambally, Zhaohui S. Qin, Arul M. Chinnaiyan^*

^*Corresponding author for this work

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

699 Scopus citations

Abstract

Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.

Original language	English (US)
Pages (from-to)	443-454
Number of pages	12
Journal	Cancer cell
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.03.018
State	Published - May 18 2010

Funding

We thank R. Mehra and B. Han for histopathologic assessment of tissue and J. Shen, S. Kalyana-Sundaram, and A. Sreekumar for technical assistance. A.M.C. is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, and the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor. This work was supported in part by the NIH Prostate Specialized Program of Research Excellence grant P50CA69568, Early Detection Research Network grant UO1 111275 (to A.M.C.), 1R01CA132874-01A1 (to A.M.C.), K99CA129565-01A1 (to J.Y.), 1R01HG005119 (to Z.Q.), P50CA090386, the Prostate Cancer Foundation (to A.M.C.), and the U.S. Department of Defense PC051081 (to A.M.C. and S.V.), and PC080665 (to J.Y.). The University of Michigan has filed for a patent on the detection of ETS gene fusions in prostate cancer, on which S.T. and A.C. are listed as coinventors. The University of Michigan licensed the diagnostic field of use of the gene fusions to Gen-Probe, Inc. S.T. has served as a consultant to Cougar Biotechnology. A.C. has served as a consultant for Gen-Probe. Gen-Probe did not play a role in the design and conduct of this study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the article.

Keywords

CELLCYCLE
DNA
SIGNALING

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.ccr.2010.03.018

Cite this

Yu, J., Yu, J., Mani, R. S., Cao, Q., Brenner, C. J., Cao, X., Wang, X., Wu, L., Li, J., Hu, M., Gong, Y., Cheng, H., Laxman, B., Vellaichamy, A., Shankar, S., Li, Y., Dhanasekaran, S. M., Morey, R., Barrette, T., ... Chinnaiyan, A. M. (2010). An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression. Cancer cell, 17(5), 443-454. https://doi.org/10.1016/j.ccr.2010.03.018

@article{df30a3e85488441d95d5c3b6f298cca8,

title = "An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression",

abstract = "Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.",

keywords = "CELLCYCLE, DNA, SIGNALING",

author = "Jindan Yu and Jianjun Yu and Mani, {Ram Shankar} and Qi Cao and Brenner, {Chad J.} and Xuhong Cao and Xiaoju Wang and Longtao Wu and James Li and Ming Hu and Yusong Gong and Hong Cheng and Bharathi Laxman and Adaikkalam Vellaichamy and Sunita Shankar and Yong Li and Dhanasekaran, {Saravana M.} and Roger Morey and Terrence Barrette and Lonigro, {Robert J.} and Tomlins, {Scott A.} and Sooryanarayana Varambally and Qin, {Zhaohui S.} and Chinnaiyan, {Arul M.}",

note = "Funding Information: We thank R. Mehra and B. Han for histopathologic assessment of tissue and J. Shen, S. Kalyana-Sundaram, and A. Sreekumar for technical assistance. A.M.C. is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, and the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor. This work was supported in part by the NIH Prostate Specialized Program of Research Excellence grant P50CA69568, Early Detection Research Network grant UO1 111275 (to A.M.C.), 1R01CA132874-01A1 (to A.M.C.), K99CA129565-01A1 (to J.Y.), 1R01HG005119 (to Z.Q.), P50CA090386, the Prostate Cancer Foundation (to A.M.C.), and the U.S. Department of Defense PC051081 (to A.M.C. and S.V.), and PC080665 (to J.Y.). The University of Michigan has filed for a patent on the detection of ETS gene fusions in prostate cancer, on which S.T. and A.C. are listed as coinventors. The University of Michigan licensed the diagnostic field of use of the gene fusions to Gen-Probe, Inc. S.T. has served as a consultant to Cougar Biotechnology. A.C. has served as a consultant for Gen-Probe. Gen-Probe did not play a role in the design and conduct of this study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the article. ",

year = "2010",

month = may,

day = "18",

doi = "10.1016/j.ccr.2010.03.018",

language = "English (US)",

volume = "17",

pages = "443--454",

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Yu, J, Yu, J, Mani, RS, Cao, Q, Brenner, CJ, Cao, X, Wang, X, Wu, L, Li, J, Hu, M, Gong, Y, Cheng, H, Laxman, B, Vellaichamy, A, Shankar, S, Li, Y, Dhanasekaran, SM, Morey, R, Barrette, T, Lonigro, RJ, Tomlins, SA, Varambally, S, Qin, ZS & Chinnaiyan, AM 2010, 'An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression', Cancer cell, vol. 17, no. 5, pp. 443-454. https://doi.org/10.1016/j.ccr.2010.03.018

TY - JOUR

T1 - An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

AU - Yu, Jindan

AU - Yu, Jianjun

AU - Mani, Ram Shankar

AU - Cao, Qi

AU - Brenner, Chad J.

AU - Cao, Xuhong

AU - Wang, Xiaoju

AU - Wu, Longtao

AU - Li, James

AU - Hu, Ming

AU - Gong, Yusong

AU - Cheng, Hong

AU - Laxman, Bharathi

AU - Vellaichamy, Adaikkalam

AU - Shankar, Sunita

AU - Li, Yong

AU - Dhanasekaran, Saravana M.

AU - Morey, Roger

AU - Barrette, Terrence

AU - Lonigro, Robert J.

AU - Tomlins, Scott A.

AU - Varambally, Sooryanarayana

AU - Qin, Zhaohui S.

AU - Chinnaiyan, Arul M.

N1 - Funding Information: We thank R. Mehra and B. Han for histopathologic assessment of tissue and J. Shen, S. Kalyana-Sundaram, and A. Sreekumar for technical assistance. A.M.C. is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, and the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor. This work was supported in part by the NIH Prostate Specialized Program of Research Excellence grant P50CA69568, Early Detection Research Network grant UO1 111275 (to A.M.C.), 1R01CA132874-01A1 (to A.M.C.), K99CA129565-01A1 (to J.Y.), 1R01HG005119 (to Z.Q.), P50CA090386, the Prostate Cancer Foundation (to A.M.C.), and the U.S. Department of Defense PC051081 (to A.M.C. and S.V.), and PC080665 (to J.Y.). The University of Michigan has filed for a patent on the detection of ETS gene fusions in prostate cancer, on which S.T. and A.C. are listed as coinventors. The University of Michigan licensed the diagnostic field of use of the gene fusions to Gen-Probe, Inc. S.T. has served as a consultant to Cougar Biotechnology. A.C. has served as a consultant for Gen-Probe. Gen-Probe did not play a role in the design and conduct of this study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the article.

PY - 2010/5/18

Y1 - 2010/5/18

N2 - Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.

AB - Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.

KW - CELLCYCLE

KW - DNA

KW - SIGNALING

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UR - http://www.scopus.com/inward/citedby.url?scp=77952103123&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2010.03.018

DO - 10.1016/j.ccr.2010.03.018

M3 - Article

C2 - 20478527

AN - SCOPUS:77952103123

SN - 1535-6108

VL - 17

SP - 443

EP - 454

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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