Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

Yu Zhao; Liguo Wang; Shancheng Ren; Lan Wang; Patrick R. Blackburn; Melissa S. McNulty; Xu Gao; Meng Qiao; Robert L. Vessella; Manish Kohli; Jun Zhang; R. Jeffrey Karnes; Donald J. Tindall; Youngsoo Kim; Robert MacLeod; Stephen C. Ekker; Tiebang Kang; Yinghao Sun; Haojie Huang

doi:10.1016/j.celrep.2016.03.038

Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

Yu Zhao, Liguo Wang, Shancheng Ren, Lan Wang, Patrick R. Blackburn, Melissa S. McNulty, Xu Gao, Meng Qiao, Robert L. Vessella, Manish Kohli, Jun Zhang, R. Jeffrey Karnes, Donald J. Tindall, Youngsoo Kim, Robert MacLeod, Stephen C. Ekker, Tiebang Kang, Yinghao Sun, Haojie Huang

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

79 Scopus citations

Abstract

The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

Original language	English (US)
Pages (from-to)	599-610
Number of pages	12
Journal	Cell reports
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2016.03.038
State	Published - Apr 19 2016
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported, in part, by grants from the NIH (CA134514, CA130908, and CA193239) and the DOD (W81XWH-09-1-622 and W81XWH-14-1-0486), a 2015 Movember Foundation-Prostate Cancer Foundation Challenge Award (2015CHAL518), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111), the National Basic Research Program of China (2012CB518300), and the National Natural Science Foundation of China (81430058) (to Y.S.); the National Natural Science Foundation of China (81472397), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator (XYQ2013077), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH (GM63904 and P30 DK84567) (to S.C.E.).

Funding Information:
This work was supported, in part, by grants from the NIH ( CA134514 , CA130908 , and CA193239 ) and the DOD ( W81XWH-09-1-622 and W81XWH-14-1-0486 ), a 2015 Movember Foundation - Prostate Cancer Foundation Challenge Award ( 2015CHAL518 ), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111 ), the National Basic Research Program of China ( 2012CB518300 ), and the National Natural Science Foundation of China ( 81430058 ) (to Y.S.); the National Natural Science Foundation of China ( 81472397 ), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator ( XYQ2013077 ), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH ( GM63904 and P30 DK84567 ) (to S.C.E.).

Publisher Copyright:
© 2016 The Authors.

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Zhao, Y., Wang, L., Ren, S., Wang, L., Blackburn, P. R., McNulty, M. S., Gao, X., Qiao, M., Vessella, R. L., Kohli, M., Zhang, J., Karnes, R. J., Tindall, D. J., Kim, Y., MacLeod, R., Ekker, S. C., Kang, T., Sun, Y., & Huang, H. (2016). Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer. Cell reports, 15(3), 599-610. https://doi.org/10.1016/j.celrep.2016.03.038

Zhao, Y, Wang, L, Ren, S, Wang, L, Blackburn, PR, McNulty, MS, Gao, X, Qiao, M, Vessella, RL, Kohli, M, Zhang, J, Karnes, RJ, Tindall, DJ, Kim, Y, MacLeod, R, Ekker, SC, Kang, T, Sun, Y & Huang, H 2016, 'Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer', Cell reports, vol. 15, no. 3, pp. 599-610. https://doi.org/10.1016/j.celrep.2016.03.038

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title = "Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer",

abstract = "The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.",

author = "Yu Zhao and Liguo Wang and Shancheng Ren and Lan Wang and Blackburn, {Patrick R.} and McNulty, {Melissa S.} and Xu Gao and Meng Qiao and Vessella, {Robert L.} and Manish Kohli and Jun Zhang and Karnes, {R. Jeffrey} and Tindall, {Donald J.} and Youngsoo Kim and Robert MacLeod and Ekker, {Stephen C.} and Tiebang Kang and Yinghao Sun and Haojie Huang",

note = "Funding Information: This work was supported, in part, by grants from the NIH (CA134514, CA130908, and CA193239) and the DOD (W81XWH-09-1-622 and W81XWH-14-1-0486), a 2015 Movember Foundation-Prostate Cancer Foundation Challenge Award (2015CHAL518), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111), the National Basic Research Program of China (2012CB518300), and the National Natural Science Foundation of China (81430058) (to Y.S.); the National Natural Science Foundation of China (81472397), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator (XYQ2013077), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH (GM63904 and P30 DK84567) (to S.C.E.). Funding Information: This work was supported, in part, by grants from the NIH ( CA134514 , CA130908 , and CA193239 ) and the DOD ( W81XWH-09-1-622 and W81XWH-14-1-0486 ), a 2015 Movember Foundation - Prostate Cancer Foundation Challenge Award ( 2015CHAL518 ), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111 ), the National Basic Research Program of China ( 2012CB518300 ), and the National Natural Science Foundation of China ( 81430058 ) (to Y.S.); the National Natural Science Foundation of China ( 81472397 ), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator ( XYQ2013077 ), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH ( GM63904 and P30 DK84567 ) (to S.C.E.). Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = apr,

day = "19",

doi = "10.1016/j.celrep.2016.03.038",

language = "English (US)",

volume = "15",

pages = "599--610",

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T1 - Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

AU - Zhao, Yu

AU - Wang, Liguo

AU - Ren, Shancheng

AU - Wang, Lan

AU - Blackburn, Patrick R.

AU - McNulty, Melissa S.

AU - Gao, Xu

AU - Qiao, Meng

AU - Vessella, Robert L.

AU - Kohli, Manish

AU - Zhang, Jun

AU - Karnes, R. Jeffrey

AU - Tindall, Donald J.

AU - Kim, Youngsoo

AU - MacLeod, Robert

AU - Ekker, Stephen C.

AU - Kang, Tiebang

AU - Sun, Yinghao

AU - Huang, Haojie

N1 - Funding Information: This work was supported, in part, by grants from the NIH (CA134514, CA130908, and CA193239) and the DOD (W81XWH-09-1-622 and W81XWH-14-1-0486), a 2015 Movember Foundation-Prostate Cancer Foundation Challenge Award (2015CHAL518), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111), the National Basic Research Program of China (2012CB518300), and the National Natural Science Foundation of China (81430058) (to Y.S.); the National Natural Science Foundation of China (81472397), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator (XYQ2013077), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH (GM63904 and P30 DK84567) (to S.C.E.). Funding Information: This work was supported, in part, by grants from the NIH ( CA134514 , CA130908 , and CA193239 ) and the DOD ( W81XWH-09-1-622 and W81XWH-14-1-0486 ), a 2015 Movember Foundation - Prostate Cancer Foundation Challenge Award ( 2015CHAL518 ), the Mayo Clinic Center for Individualized Medicine Pilot Award, and the Mayo Clinic Center for Biomedical Discovery Platform Grant (to H.H.); the T.J. Martell Foundation (to D.J.T. and H.H.); the Program for Changjiang Scholars (No. IRT1111 ), the National Basic Research Program of China ( 2012CB518300 ), and the National Natural Science Foundation of China ( 81430058 ) (to Y.S.); the National Natural Science Foundation of China ( 81472397 ), Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator ( XYQ2013077 ), and Shanghai Municipal Education Commission (to S.R.); and grants from the NIH ( GM63904 and P30 DK84567 ) (to S.C.E.). Publisher Copyright: © 2016 The Authors.

PY - 2016/4/19

Y1 - 2016/4/19

N2 - The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

AB - The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

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ER -

Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

Abstract

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