Review
The emerging role of histone lysine demethylases in prostate cancer
1 Experimental Therapeutics, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3
2 Department of Internal Medicine, Division of Pharmacology, University of Pisa, Via Roma 55, 56100 Pisa, Italy
3 Cancer Stem Cell Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Building 560, Room 21-81, Frederick, MD 21702, USA
4 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 5, 00185 Rome, Italy
5 Department of Surgery, Faculty of Medicine, University of British Columbia, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 4E3
Molecular Cancer 2012, 11:52 doi:10.1186/1476-4598-11-52
Published: 6 August 2012Abstract
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.
