Hormonal Therapy Promotes Hormone-Resistant Phenotype by Increasing DNMT Activity and Expression in Prostate Cancer Models
G. Gravina1,6, C. Festuccia1, M. Piccolella2, M. Motta2, L. Ventura3, R. Pomante5, B. Zani1, R. Pestell4, V. Tombolini1, A. Lenzi6 & E. Jannini1
We hypothesized that hormonal therapy favors the development of the hormone-resistant (HR) phenotype through epigenetic mechanisms. Human prostate cancer (Pca) tissues and in vitro and in vivo models were used to verify this hypothesis. We demonstrated that tumor cells continuously treated with BCLT or cultured in androgen depleted medium progressively acquire higher DNMT activity and expression. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms which favors the development of the HR phenotype. Following DHT stimulation, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3-a and DNMT3-b significantly decreased the DNMT activity levels. These findings were also directly correlated with PTEN down-regulation and activation of ERK and PI3K/Akt pathways. The use of a pan-DNMT inhibitor (5-Azaciticine) greatly reduced the development of the HR phenotype induced by long-term BCLT treatment and this finding correlated with DNMT activity decrease. The regulation of DNMT activity was, in some measure, dependent on the AR, as siRNA treatment targeting the AR 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 prior to surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the HR phenotype and DNMT in human Pca.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.