title: Hormonal therapy promotes hormone-resistant phenotype by increasing DNMT activity and expression in prostate cancer models.
abstract: We hypothesized that hormonal therapy favors the development of the hormone-resistant phenotype through epigenetic mechanisms. Human prostate cancer tissues and in vitro and in vivo models were used to verify this hypothesis. We demonstrated that tumor cells continuously treated with bicalutamide (BCLT) or cultured in androgen-depleted medium progressively acquire higher DNA methyltransferase (DNMT) activity and expression than cells cultured in standard condition. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms, which favors the development of the hormone-resistant phenotype. After androgen stimulation with 10(-12) m dihydrotestosterone, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3a and DNMT3b significantly decreased the DNMT activity levels. These findings were also directly correlated with phosphatase and tensin homolog down-regulation and activation of ERK and phosphatidylinositol 3-kinases/AKT8 virus oncogene cellular homolog pathways. The use of a pan-DNMT inhibitor (5-Azacitidine) greatly reduced the development of the hormone-resistant phenotype induced by long-term BCLT treatment, and this finding correlated with low DNMT activity. The regulation of DNMT activity was, in some measure, dependent on the androgen receptor, as small interfering RNA treatment targeting the androgen receptor greatly decreased the modulation of DNMT activity under androgenic and antiandrogenic stimulation. These observations were correlated in vivo in patients, as demonstrated by immunohistochemistry. Patients treated by BCLT before surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the castration-resistant phenotype and DNMT expression and activity in human prostate cancer.
authors: Department of Experimental Medicine, Division of Radiotherapy and Radiobiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy. giovanniluca.gravina@poste.it
authors: Giovanni Luca
authors: GL
authors: Gravina
authors: Francesco
authors: F
authors: Marampon
authors: Margherita
authors: M
authors: Piccolella
authors: Marcella
authors: M
authors: Motta
authors: Luca
authors: L
authors: Ventura
authors: Roberto
authors: R
authors: Pomante
authors: Vladimir M
authors: VM
authors: Popov
authors: Bianca M
authors: BM
authors: Zani
authors: Richard G
authors: RG
authors: Pestell
authors: Vincenzo
authors: V
authors: Tombolini
authors: Emmanuele A
authors: EA
authors: Jannini
authors: Claudio
authors: C
authors: Festuccia
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004351:Drug Resistance; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000097584:DNA Methyltransferase 3B
chemical_list: D000813:Anilides; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006728:Hormones; D009570:Nitriles; D014105:Tosyl Compounds; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C053541:bicalutamide