Prostate cancer is one of the most notorious male cancers in the world. The disease is becoming increasingly burdensome for families, healthcare systems, and the patients themselves. Current popular treatments have several critical issues with one of the most devastating being prostate cancer becoming drastically more aggressive and castration-resistant after androgen deprivation therapy through a process known as neuroendocrine differentiation (NED),which significantly shortens the lifespan of the patient. The epigenetic mechanisms by which these prostate cancer cells become castration-resistant have not been fully elucidated. AR, histone demethylases, and microRNAs (miRNAs) have all been implicated in several cancers, but little is known about how these epigenetic components interact in prostate cancer. We are particularly concerned with the orchestration of these molecules before, during, and after NED in order to attain a rolling view of the phenotypical changes in gene expression that accompany this process. An in-vitro cell model was utilized to establish IL-6 and androgen-dependent cells. Castration-resistant prostate cancer (CRPC) cell lines included androgen-deprivation and IL-6 supplementation treatment for at least 1 year. PCR, RT-PCR, and qPCR was utilized to evaluate potential associations between mRNA profiles of several histone demethylases (KDMs) and miRNAs , while Western blots were utilized to monitor the regulation of the selected KDMs. Identifying strong associations between miRNAs and KDMs within the NED process could give rise to novel diagnostic markers for gauging CRPC potential in patients, which can lead to a significant improvement in homogeneity between diagnosis and outcomes. Also, the discovery of certain KDMs as novel drug targets could implicate better prevention and possibly the amelioration of prostate cancer cells’ transition to castration-resistance.