Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer

Mari Björkman (Corresponding Author), Kristiina Iljin, Pasi Halonen, Henri Sara, Elisa Kaivanto, Matthias Nees, Olli Kallioniemi

Research output: Contribution to journalArticleScientificpeer-review

51 Citations (Scopus)

Abstract

Gene fusions between prostate‐specific, androgen responsive TMPRSS2 gene and oncogenic ETS factors, such as ERG, occur in up to 50% of all prostate cancers. We recently defined a gene signature that was characteristic to prostate cancers with ERG activation. This suggested epigenetic reprogramming, such as upregulation of histone deactylase 1 (HDAC1) gene and downregulation of its target genes. We then hypothesized that patients with ERG‐positive prostate cancers may benefit from epigenetic therapy such as HDAC inhibition (HDACi), especially in combination with antiandrogens. Here, we exposed ERG‐positive prostate cancer cell lines to HDAC inhibitors Trichostatin A (TSA), MS‐275 and suberoylanilide hydroxamic acid (SAHA) with or without androgen deprivation. We explored the effects on cell phenotype, gene expression as well as ERG and androgen receptor (AR) signaling. When compared with 5 other prostate cell lines, ERG‐positive VCaP and DuCap cells were extremely sensitive to HDACi, in particular TSA, showing synergy with concomitant androgen deprivation increasing apoptosis. Both of the HDAC inhibitors studied caused repression of the ERG‐fusion gene, whereas the pan‐HDAC inhibitor TSA prominently repressed the ERG‐associated gene signature. Additionally, HDACi and flutamide caused retention of AR in the cytoplasm, indicating blockage of androgen signaling. Our results support the hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2‐ERG‐fusion positive prostate cancer in vitro. Together with our previous in vivo observations of an “epigenetic reprogramming gene signature” in clinical ERG‐positive prostate cancers, these studies provide mechanistic insights to ERG‐associated tumorigenesis and suggest therapeutic paradigms to be tested in vivo.
Original languageEnglish
Pages (from-to)2774-2781
Number of pages8
JournalInternational Journal of Cancer
Volume123
Issue number12
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fingerprint

Histone Deacetylase Inhibitors
Androgens
Prostatic Neoplasms
trichostatin A
Genes
Epigenomics
Androgen Receptors
Flutamide
Androgen Antagonists
Cell Line
Gene Fusion
Histones
Prostate
Carcinogenesis
Cytoplasm
Up-Regulation
Down-Regulation
Apoptosis
Phenotype
Gene Expression

Keywords

  • ERG
  • HDAC inhibitors
  • prostate cancer
  • AR

Cite this

Björkman, Mari ; Iljin, Kristiina ; Halonen, Pasi ; Sara, Henri ; Kaivanto, Elisa ; Nees, Matthias ; Kallioniemi, Olli. / Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. In: International Journal of Cancer. 2008 ; Vol. 123, No. 12. pp. 2774-2781.
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abstract = "Gene fusions between prostate‐specific, androgen responsive TMPRSS2 gene and oncogenic ETS factors, such as ERG, occur in up to 50{\%} of all prostate cancers. We recently defined a gene signature that was characteristic to prostate cancers with ERG activation. This suggested epigenetic reprogramming, such as upregulation of histone deactylase 1 (HDAC1) gene and downregulation of its target genes. We then hypothesized that patients with ERG‐positive prostate cancers may benefit from epigenetic therapy such as HDAC inhibition (HDACi), especially in combination with antiandrogens. Here, we exposed ERG‐positive prostate cancer cell lines to HDAC inhibitors Trichostatin A (TSA), MS‐275 and suberoylanilide hydroxamic acid (SAHA) with or without androgen deprivation. We explored the effects on cell phenotype, gene expression as well as ERG and androgen receptor (AR) signaling. When compared with 5 other prostate cell lines, ERG‐positive VCaP and DuCap cells were extremely sensitive to HDACi, in particular TSA, showing synergy with concomitant androgen deprivation increasing apoptosis. Both of the HDAC inhibitors studied caused repression of the ERG‐fusion gene, whereas the pan‐HDAC inhibitor TSA prominently repressed the ERG‐associated gene signature. Additionally, HDACi and flutamide caused retention of AR in the cytoplasm, indicating blockage of androgen signaling. Our results support the hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2‐ERG‐fusion positive prostate cancer in vitro. Together with our previous in vivo observations of an “epigenetic reprogramming gene signature” in clinical ERG‐positive prostate cancers, these studies provide mechanistic insights to ERG‐associated tumorigenesis and suggest therapeutic paradigms to be tested in vivo.",
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Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. / Björkman, Mari (Corresponding Author); Iljin, Kristiina; Halonen, Pasi; Sara, Henri; Kaivanto, Elisa; Nees, Matthias; Kallioniemi, Olli.

In: International Journal of Cancer, Vol. 123, No. 12, 2008, p. 2774-2781.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer

AU - Björkman, Mari

AU - Iljin, Kristiina

AU - Halonen, Pasi

AU - Sara, Henri

AU - Kaivanto, Elisa

AU - Nees, Matthias

AU - Kallioniemi, Olli

PY - 2008

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N2 - Gene fusions between prostate‐specific, androgen responsive TMPRSS2 gene and oncogenic ETS factors, such as ERG, occur in up to 50% of all prostate cancers. We recently defined a gene signature that was characteristic to prostate cancers with ERG activation. This suggested epigenetic reprogramming, such as upregulation of histone deactylase 1 (HDAC1) gene and downregulation of its target genes. We then hypothesized that patients with ERG‐positive prostate cancers may benefit from epigenetic therapy such as HDAC inhibition (HDACi), especially in combination with antiandrogens. Here, we exposed ERG‐positive prostate cancer cell lines to HDAC inhibitors Trichostatin A (TSA), MS‐275 and suberoylanilide hydroxamic acid (SAHA) with or without androgen deprivation. We explored the effects on cell phenotype, gene expression as well as ERG and androgen receptor (AR) signaling. When compared with 5 other prostate cell lines, ERG‐positive VCaP and DuCap cells were extremely sensitive to HDACi, in particular TSA, showing synergy with concomitant androgen deprivation increasing apoptosis. Both of the HDAC inhibitors studied caused repression of the ERG‐fusion gene, whereas the pan‐HDAC inhibitor TSA prominently repressed the ERG‐associated gene signature. Additionally, HDACi and flutamide caused retention of AR in the cytoplasm, indicating blockage of androgen signaling. Our results support the hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2‐ERG‐fusion positive prostate cancer in vitro. Together with our previous in vivo observations of an “epigenetic reprogramming gene signature” in clinical ERG‐positive prostate cancers, these studies provide mechanistic insights to ERG‐associated tumorigenesis and suggest therapeutic paradigms to be tested in vivo.

AB - Gene fusions between prostate‐specific, androgen responsive TMPRSS2 gene and oncogenic ETS factors, such as ERG, occur in up to 50% of all prostate cancers. We recently defined a gene signature that was characteristic to prostate cancers with ERG activation. This suggested epigenetic reprogramming, such as upregulation of histone deactylase 1 (HDAC1) gene and downregulation of its target genes. We then hypothesized that patients with ERG‐positive prostate cancers may benefit from epigenetic therapy such as HDAC inhibition (HDACi), especially in combination with antiandrogens. Here, we exposed ERG‐positive prostate cancer cell lines to HDAC inhibitors Trichostatin A (TSA), MS‐275 and suberoylanilide hydroxamic acid (SAHA) with or without androgen deprivation. We explored the effects on cell phenotype, gene expression as well as ERG and androgen receptor (AR) signaling. When compared with 5 other prostate cell lines, ERG‐positive VCaP and DuCap cells were extremely sensitive to HDACi, in particular TSA, showing synergy with concomitant androgen deprivation increasing apoptosis. Both of the HDAC inhibitors studied caused repression of the ERG‐fusion gene, whereas the pan‐HDAC inhibitor TSA prominently repressed the ERG‐associated gene signature. Additionally, HDACi and flutamide caused retention of AR in the cytoplasm, indicating blockage of androgen signaling. Our results support the hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2‐ERG‐fusion positive prostate cancer in vitro. Together with our previous in vivo observations of an “epigenetic reprogramming gene signature” in clinical ERG‐positive prostate cancers, these studies provide mechanistic insights to ERG‐associated tumorigenesis and suggest therapeutic paradigms to be tested in vivo.

KW - ERG

KW - HDAC inhibitors

KW - prostate cancer

KW - AR

U2 - 10.1002/ijc.23885

DO - 10.1002/ijc.23885

M3 - Article

VL - 123

SP - 2774

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JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

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ER -