Department of Experimental Medicine; Division of Radiotherapy, Laboratory of Radiobiology; and Course of Endocrinology and Medical Sexology, Department of Experimental Medicine, University of L'Aquila, Italy.
Department of Pathology, San Salvatore Hospital, 67100 L'Aquila, Italy; Department of Endocrinology, Center of Endocrinological Oncology, University of Milano, 20122 Milan, Italy; Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Department of Pathology, Mazzini Hospital, 64100 Teramo, Italy; Department of Radiological Sciences, University of Rome "La Sapienza" Spencer-Lorillard Fondation, 00100 Rome, Italy.
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.
Written by:
Gravina GL, Marampon F, Piccolella M, Motta M, Ventura L, Pomante R, Popov VM, Zani BM, Pestell RG, Tombolini V, Jannini EA, Festuccia C. Are you the author?
Reference: Endocrinology. 2011 Oct 11. Epub ahead of print.
doi: 10.1210/en.2011-1056
PubMed Abstract
PMID: 21990314
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