The emerging role of histone lysine demethylases in prostate cancer

Abstract

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.

Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase

“…www.impactjournals.com/oncotarget Metastasis suppressor genes (MSGs) are negative regulators of metastasis [10,11]. Compelling evidence indicates that modifications of DNA methylation and histones can silence the expression of MSGs, leading to the development of metastasis [12][13][14]. This notion is supported by studies of CRMP4, a novel prostate cancer MSG recently identified by our laboratory [15].…”

Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer

“…As homeobox genes are master regulators, one possibility is that DNA methylation disturbs PRC-mediated regulation and may create a more stable silent state as opposed to a more dynamic state. Histone methylation, including H3K27me3, can be removed via well-known histone demethylases (47), whereas active DNA demethylation seems to be a more cumbersome process involving hydroxymethylation and DNA repair pathways (48,49). Another possibility is that genes with PRC marks in benign prostate cells are particularly susceptible to DNA methylation in prostate cancer, but that the latter is merely a by-product of overactive DNA methylation machinery.…”

Silver nanoparticle-induced hemoglobin decrease involves alteration of histone 3 methylation status

“…Thus, the methylation level of lysine in histone is determined by the net activity of histone lysine methyltransferases and demethylases [43,60]. Dysfunction of these enzymes would give rise to abnormal histone methylation, possibly associated with disordered gene expression and even development of various diseases [59,61,62]. However, little effort has been made to elaborate a likely disturbance of histone methylation by nanomaterials.…”