Role of epigenetic therapy in the modulation of tumor growth and migration in human castration resistance prostate cancer cells with neuroendocrine differentiation

ABSTRACT: Neuroendocrine transdifferentiation (NED) of prostate cancer cells and aberrant activation of survival pathways involved in tumorigenesis are among the events that lead to the development of resistance to anti-androgen therapy and are associated with poor prognosis in patients with castration resistance prostate cancer (CRPC). Most of these molecular events appear to be mediated by epigenetic mechanisms, in particular DNA methylation. In this study, we evaluated the antitumor activity and epigenetic modulation of two epigenetic drugs, 5-aza-2’-deoxycytidine (AZA) and S-adenosylmethionine (SAM) in two human CRPC cell lines with NED (NED-CRPC), DU-145 and PC-3. The effects of AZA and SAM on the cell growth proliferation, cell cycle, apoptosis, migration and genome-wide DNA methylation profiling have been evaluated through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, wound-healing assay and Infinium450k microarray, respectively. Both epigenetic drugs showed a prominent antitumor activity in NED-CRPC cell line exerted through perturbation of cell cycle progression, induction of apoptosis and migration arrest. AZA and SAM reversed NED in DU-145 and PC-3, respectively. Moreover, AZA treatment profoundly modified DNA methylation pattern, sustaining a pervasive hypomethylation of the genome, with a relevant effect on several pathways involved in regulation of cell migration, cell proliferation and apoptosis. Among these, the Wnt/beta-catenin signaling appeared to be the most directly involved. In conclusion, both AZA and SAM showed a relevant antitumor activity on NED-CRPC cell lines. This opens a new scenario in the therapy of this lethal variant of prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164249 | GEO | 2023/01/13

REPOSITORIES: GEO