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 & 15 others 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

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages2045-2059
Number of pages15
JournalCell Reports
Volume19
Issue number10
DOIs
StatePublished - Jun 6 2017

Fingerprint

Deregulation
Androgen Receptors
Chromatin
Prostatic Neoplasms
Transcription Factors
Acetylation
Histones
Androgens
Castration
Proteins
Drug Delivery Systems
Genes
Neoplasms
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Urbanucci, A., Barfeld, S. J., Kytölä, V., Itkonen, H. M., Coleman, I. M., Vodák, D., ... Mills, I. G. (2017). Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Reports, 19(10), 2045-2059. DOI: 10.1016/j.celrep.2017.05.049

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

In: Cell Reports, Vol. 19, No. 10, 06.06.2017, p. 2045-2059.

Research output: Contribution to journalArticle

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. DOI: 10.1016/j.celrep.2017.05.049
Urbanucci A, Barfeld SJ, Kytölä V, Itkonen HM, Coleman IM, Vodák D et al. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Reports. 2017 Jun 6;19(10):2045-2059. Available from, DOI: 10.1016/j.celrep.2017.05.049
Urbanucci, Alfonso ; Barfeld, Stefan J. ; Kytölä, Ville ; Itkonen, Harri M. ; Coleman, Ilsa M. ; Vodák, Daniel ; Sjöblom, Liisa ; Sheng, Xia ; Tolonen, Teemu ; Minner, Sarah ; Burdelski, Christoph ; Kivinummi, Kati K. ; Kohvakka, Annika ; Kregel, Steven ; Takhar, Mandeep ; Alshalalfa, Mohammed ; Davicioni, Elai ; Erho, Nicholas ; Lloyd, Paul ; Karnes, R. Jeffrey ; Ross, Ashley E. ; Schaeffer, Edward M. ; Vander Griend, Donald J. ; Knapp, Stefan ; Corey, Eva ; Feng, Felix Y. ; Nelson, Peter S. ; Saatcioglu, Fahri ; Knudsen, Karen E. ; Tammela, Teuvo L.J. ; Sauter, Guido ; Schlomm, Thorsten ; Nykter, Matti ; Visakorpi, Tapio ; Mills, Ian G./ Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. In: Cell Reports. 2017 ; Vol. 19, No. 10. pp. 2045-2059
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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.",
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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.

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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.

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