title: Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer.
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.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, Institute for Molecular Medicine Finland and University of Turku, Turku, Finland. ext-mari.bjorkman@vtt.fi
authors.forename: Mari
authors.initials: M
authors.lastname: Björkman
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Pasi
authors.initials: P
authors.lastname: Halonen
authors.forename: Henri
authors.initials: H
authors.lastname: Sara
authors.forename: Elisa
authors.initials: E
authors.lastname: Kaivanto
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.forename: Olli P
authors.initials: OP
authors.lastname: Kallioniemi
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000032:analysis*; D016133:Polymerase Chain Reaction / Q000379:methods; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics; D014105:Tosyl Compounds / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D014105:Tosyl Compounds; C118739:entinostat; C012589:trichostatin A; C053541:bicalutamide