Early
prostate cancer (PCa) is generally treatable and associated with good prognosis. After a variable time, PCa evolves into a highly metastatic and treatment-refractory disease:
castration-resistant PCa (CRPC). Currently, few prognostic factors are available to predict the emergence of CRPC, and no curative option is available. Epigenetic gene regulation has been shown to trigger PCa
metastasis and
androgen-independence. Most epigenetic studies have focused on
DNA and
histone methyltransferases. While DNA methylation leads to gene silencing,
histone methylation can trigger gene activation or inactivation, depending on the target
amino acid residues and the extent of methylation (me1, me2, or me3). Interestingly, some
histone modifiers are essential for PCa tumor-initiating cell (
TIC) self-renewal.
TICs are considered the seeds responsible for metastatic spreading and
androgen-independence.
Histone Lysine Demethylases (KDMs) are a novel class of epigenetic
enzymes which can remove both repressive and activating histone marks. KDMs are currently grouped into 7 major classes, each one targeting a specific methylation site. Since their discovery, KDM expression has been found to be deregulated in several
neoplasms. In PCa, KDMs may act as either
tumor suppressors or oncogenes, depending on their gene regulatory function. For example, KDM1A and KDM4C are essential for PCa
androgen-dependent proliferation, while PHF8 is involved in PCa migration and invasion. Interestingly, the possibility of pharmacologically targeting KDMs has been demonstrated. In the present paper, we summarize the emerging role of KDMs in regulating the metastatic potential and
androgen-dependence of PCa. In addition, we speculate on the possible interaction between KDMs and other epigenetic effectors relevant for PCa
TICs. Finally, we explore the role of KDMs as novel prognostic factors and therapeutic targets. We believe that studies on
histone demethylation may add a novel perspective in our efforts to prevent and cure advanced PCa.