Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Alfonso Urbanucci; Stefan J. Barfeld; Ville Kytölä; Harri M. Itkonen; Ilsa M. Coleman; Daniel Vodák; Liisa Sjöblom; Xia Sheng; Teemu Tolonen; Sarah Minner; Christoph Burdelski; Kati K. Kivinummi; Annika Kohvakka; Steven Kregel; Mandeep Takhar; Mohammed Alshalalfa; Elai Davicioni; Nicholas Erho; Paul Lloyd; R. Jeffrey Karnes; Ashley E. Ross; Edward M. Schaeffer; Donald J. Vander Griend; Stefan Knapp; Eva Corey; Felix Y. Feng; Peter S. Nelson; Fahri Saatcioglu; Karen E. Knudsen; Teuvo L.J. Tammela; Guido Sauter; Thorsten Schlomm; Matti Nykter; Tapio Visakorpi; Ian G. Mills

doi:10.1016/j.celrep.2017.05.049

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Alfonso Urbanucci, Stefan J. Barfeld, Ville Kytölä, Harri M. Itkonen, Ilsa M. Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K. Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R. Jeffrey KarnesAshley E. Ross, Edward M. Schaeffer, Donald J. Vander Griend, Stefan Knapp, Eva Corey, Felix Y. Feng, Peter S. Nelson, Fahri Saatcioglu, Karen E. Knudsen, Teuvo L.J. Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G. Mills

School of Medicine

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

51 Scopus citations

Abstract

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Original language	English (US)
Pages (from-to)	2045-2059
Number of pages	15
Journal	Cell Reports
Volume	19
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2017.05.049
State	Published - Jun 6 2017

Keywords

androgen receptor
ATAD2
BRD2
BRD4
BROMO-10
bromodomain inhibitor
castration-resistant prostate cancer
chromatin

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2017.05.049

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Urbanucci, A., Barfeld, S. J., Kytölä, V., Itkonen, H. M., Coleman, I. M., Vodák, D., Sjöblom, L., Sheng, X., Tolonen, T., Minner, S., Burdelski, C., Kivinummi, K. K., Kohvakka, A., Kregel, S., Takhar, M., Alshalalfa, M., Davicioni, E., Erho, N., Lloyd, P., ... Mills, I. G. (2017). Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Reports, 19(10), 2045-2059. https://doi.org/10.1016/j.celrep.2017.05.049

Urbanucci, A, Barfeld, SJ, Kytölä, V, Itkonen, HM, Coleman, IM, Vodák, D, Sjöblom, L, Sheng, X, Tolonen, T, Minner, S, Burdelski, C, Kivinummi, KK, Kohvakka, A, Kregel, S, Takhar, M, Alshalalfa, M, Davicioni, E, Erho, N, Lloyd, P, Karnes, RJ, Ross, AE, Schaeffer, EM, Vander Griend, DJ, Knapp, S, Corey, E, Feng, FY, Nelson, PS, Saatcioglu, F, Knudsen, KE, Tammela, TLJ, Sauter, G, Schlomm, T, Nykter, M, Visakorpi, T & Mills, IG 2017, 'Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer', Cell Reports, vol. 19, no. 10, pp. 2045-2059. https://doi.org/10.1016/j.celrep.2017.05.049

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title = "Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer",

abstract = "Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.",

keywords = "androgen receptor, ATAD2, BRD2, BRD4, BROMO-10, bromodomain inhibitor, castration-resistant prostate cancer, chromatin",

author = "Alfonso Urbanucci and Barfeld, {Stefan J.} and Ville Kyt{\"o}l{\"a} and Itkonen, {Harri M.} and Coleman, {Ilsa M.} and Daniel Vod{\'a}k and Liisa Sj{\"o}blom and Xia Sheng and Teemu Tolonen and Sarah Minner and Christoph Burdelski and Kivinummi, {Kati K.} and Annika Kohvakka and Steven Kregel and Mandeep Takhar and Mohammed Alshalalfa and Elai Davicioni and Nicholas Erho and Paul Lloyd and Karnes, {R. Jeffrey} and Ross, {Ashley E.} and Schaeffer, {Edward M.} and {Vander Griend}, {Donald J.} and Stefan Knapp and Eva Corey and Feng, {Felix Y.} and Nelson, {Peter S.} and Fahri Saatcioglu and Knudsen, {Karen E.} and Tammela, {Teuvo L.J.} and Guido Sauter and Thorsten Schlomm and Matti Nykter and Tapio Visakorpi and Mills, {Ian G.}",

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T1 - Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

AU - Urbanucci, Alfonso

AU - Barfeld, Stefan J.

AU - Kytölä, Ville

AU - Itkonen, Harri M.

AU - Coleman, Ilsa M.

AU - Vodák, Daniel

AU - Sjöblom, Liisa

AU - Sheng, Xia

AU - Tolonen, Teemu

AU - Minner, Sarah

AU - Burdelski, Christoph

AU - Kivinummi, Kati K.

AU - Kohvakka, Annika

AU - Kregel, Steven

AU - Takhar, Mandeep

AU - Alshalalfa, Mohammed

AU - Davicioni, Elai

AU - Erho, Nicholas

AU - Lloyd, Paul

AU - Karnes, R. Jeffrey

AU - Ross, Ashley E.

AU - Schaeffer, Edward M.

AU - Vander Griend, Donald J.

AU - Knapp, Stefan

AU - Corey, Eva

AU - Feng, Felix Y.

AU - Nelson, Peter S.

AU - Saatcioglu, Fahri

AU - Knudsen, Karen E.

AU - Tammela, Teuvo L.J.

AU - Sauter, Guido

AU - Schlomm, Thorsten

AU - Nykter, Matti

AU - Visakorpi, Tapio

AU - Mills, Ian G.

PY - 2017/6/6

Y1 - 2017/6/6

N2 - Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

AB - Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

KW - androgen receptor

KW - ATAD2

KW - BRD2

KW - BRD4

KW - BROMO-10

KW - bromodomain inhibitor

KW - castration-resistant prostate cancer

KW - chromatin

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DO - 10.1016/j.celrep.2017.05.049

M3 - Article

C2 - 28591577

AN - SCOPUS:85020289723

SN - 2211-1247

VL - 19

SP - 2045

EP - 2059

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Abstract

Keywords

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