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Targeting The Prostate Cancer Epigenome

Paper Type: Free Essay Subject: Biology
Wordcount: 5360 words Published: 2nd May 2017

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The initiation and progression of cancer is regulated by both genetic and epigenetic events such as DNA methylation, histone deacetylation and nucleosome remodelling. Abnormal regulation of such events promotes genomic instability, silencing of tumour suppressor genes and oncogene activation. Genetic alterations are almost impossible to reverse whereas abnormal epigenetic modifications are reversible, allowing the malignant cell population to return to a normal state. Epigenetic modifications, a hallmark of cancer, provide an exciting avenue for cancer research.

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Prostate cancer is amongst the most commonly diagnosed and leading causes of cancer related deaths in men in the western world. Primary stage and localized prostate cancer has a positive curative outcome due the development of early screening techniques and therapies. However, advanced/castration-resistant prostate cancer is associated with recurrence, metastasis and poor survival. As a result, a successful therapy is urgently needed.

The focus of this review is on histone deacetylase and histone lysine demethylase inhibitors as a possible therapeutic for prostate cancer. Histone deacetylase inhibitors are considered to be among the most promising targets in cancer drug development with ample research showing substantial anti-proliferative and apoptotic properties on a variety of cancer cells, including prostate. The discovery of an increased number of histone lysine demethylases highlighted the dynamic nature of histone methylation regulation. There is significantly less research on histone lysine demethylase inhibitors in comparison to histone deacetylase inhibitors, yet they too look promising. Reactivation of tumour suppressor genes and prevention of oncogenesis through the inhibition of deacetylation and demethylation agents could be a potential treatment for prostate cancer, especially advanced disease.


Prostate cancer is the most frequently diagnosed male neoplasm and the second leading cause of cancer related deaths in men in the Western world [1]. The increased incidence of prostate cancer in recent years may be a result of improved understanding of the pathogenesis of prostate cancer, population based screening by PSA and elevated life expectancy. Prostate cancer has been described as a double stage disease which usually starts as a treatable and poorly aggressive cancer that can be alleviated with chemotherapy, radiotherapy and/or hormonal therapy [2]. Advanced stage disease, known as castration-resistant prostate cancer is associated with poor outcome. It involves disruption of the androgen receptor signalling which is a major proliferation stress for prostate cancer cells. It is also related to metastatic spread of prostate cancer to brain, liver and bones in ninety percent of cases and on average displays an eighteen month survival [3].

Castration-resistant prostate cancer is a much more aggressive cancer associated with poor prognosis and survival. This form of prostate cancer is resistant to conventional treatment with chemotherapy suggested to only delay progression[3]. Thus, considering that approximately 250,000 men are affected with prostate cancer annually, there is dire need to develop a novel treatment which will provide prolonged survival, prevent recurrence and prevent progression to castration-resistant prostate cancer. Research conducted over the past twenty years has revealed that prostate cancer is not only driven by genetic alterations but by epigenetic modifications also. Much research into the field of epigenetic research has provided promising avenues for potential therapeutic and prognostic roles in prostate cancer. This review proposes to evaluate emerging evidence on the role of histone deacetylation inhibitors and histone lysine demethylation inhibitors in prostate cancer, and to propose their role in prognostics and therapy.


Epigenetics is used to describe mitotically and meiotically heritable changes in gene expression which do not alter the DNA sequence. There has been a wealth of research into the field of epigenetics in the past twenty years revealing that epigenetics plays a functional in almost every biological process. The heritability of gene expression patterns is mediated by epigenetic modifications which include DNA methylation, histone modification and nucleosome remodelling. These epigenetic modifications are collectively referred to as the epigenome. Failure of accurate regulation of epigenetic modifications can result in genome instability, inaccurate activation or inhibition or various signalling pathways and can lead to disease epidemics, such as cancer [4, 5] and prostate cancer [6].


Figure 1: Illustration of epigenetic modifications, DNA methylation and histone modifications, clearing showing DNA wrapped around histones, with protruding histone tails [7].


DNA methylation is the most elucidated epigenetic modification. It provides a stable gene silencing mechanism which plays an important role in regulating gene expression and chromatin architecture, in association with histone modification and other chromatin associated proteins [6, 8].

DNA is methylated by DNA methyltranferases (DNMTs) which are responsible for the binding of a methyl group to the 5’C position in cytosine, generating 5mC. DNA methyltranferases are a family of enzymes, termed DNMTs. DNMT3A and DNMT3B have functional roles in de novo methylation, whereas DNMT1 is required for normal methylation maintenance throughout the genome [6]. DNMTs also play a role in the regulation of CpG island methylation [9]. CpG islands are generally located at the 5′ end, including the promoter, un-translated region and first exon of approximately sixty percent of the human genome. Hypermethylation in the promoter CpG islands is associated with gene silencing, while hypomethylation is associated with increased gene expression. The delicate balance between hypermethylation and hypomethylation of promoter regions is a key component of gene expression regulation in both genomic imprinting and X-chromosome inactivation [6, 10].

With elevated age, changes in global methylation are apparent which contribute to prostate cancer development and progression [6, 11]. These global methylation changes can result in hypermethylation of CpG island residues leading to the inactivation of tumour suppressor genes and activation of oncogenes. Cooper and Foster constructed a complete list of such hypermethylated genes in a minireview looking at the concepts of epigenetics in prostate cancer development [11]. Inappropriate hypermethylation and inactivation of genes such as INK4a, RASSF1a and APC are associated with early prostate cancer development [11]. Methylation can also be associated with tumour progression. E cadherin is a key player in cell adhesion, thus hypermethylation plays an important role in the transition of epithelial to mesenchymal morphology and behaviour of prostate cancer – resulting in tumour progression [12]. Li and colleagues also reported that methylation of the ESR1 gene, a gene when down-regulated is associated with metastasis, is expressed in prostate cancer [13]. Evidence also illustrates that nuclear hormone receptors, such as the androgen receptor (AR) is hypermethylated in prostate cancer patients which is of little surprise considering the role AR plays in prostate cancer. Hypomethylation resulting in up-regulation of oncogenes such as WNT5A, CRIP1 and S100P have too been strongly associated with prostate cancer [14].


DNA is wrapped around a core of eight histones to form nucleosomes. Nucleosomes can be classified as the basic building blocks of chromatin as each one is composed of approximately 146 base pairs of DNA wrapped around a histone octamer that consists of two copies of each of H2A, H2B, H3 and H4. The amino-terminal tails of histones protrude out of the nucleosome which makes them subject to multiple post-translational modifications – including phosphorylation, sumoylation, ubiquitination, acetylation and methylation. Histone modifications can lead to either activation (open) or repression (closed) depending on the type of residue which is adapted and the modifications present. These histone modifications ultimately change the conformation of the nucleosome which has a vital role in regulating key cellular processes such as transcription, replication and repair [15].

Proteins which are involved in the modification of histone tail residues by acetylation or methylation are referred to as ‘writers’ and ‘erasers’. ‘Writers’ are involved in the addition of a chemical mark to a histone substrate, examples being histone acetyltranferases (HATs) and methyltranferases (HMTs). ‘Erasers’ on the other hand can be described as removing modifications from histone in the form of histone deacetylases (HDACs) and histone lysine demethylases (KDMs). Proteins which are involved in recognizing and reacting to specific histone modifications on an epigenetic level can be referred to as ‘readers’ [15-17].


Histone acetylation is the most extensively studied histone modification. Acetylation is a key posttranslational modification which involves the alteration of many proteins responsible for regulating critical intracellular pathways. Acetylation involves the addition of an acetyl group to the lysine residue of the N-terminal tail of the nucleosome core [18]. Histone acetylation, like all genetic modifications, is tightly regulated. Histone acetyl transferases (HATs) are family of enzymes which play a vital role in the addition of an acetyl group, which results in local chromatin expansion and increased accessibility of DNA to regulatory proteins [15]. Acetylation is associated ‘open’ chromatin, influencing active transcription [10].


Figure 2: Systematic illustration of histone acetylation and histone deacetylation [19]

Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from lysine residues in the histone amino terminal, leading to chromatin condensation and transcriptional repression [20], including a decrease in the expression of tumour suppressor genes [21]. In comparison to acetylation, deacetylation correlates with gene silencing. HDACs primarily target histone proteins but are also involved in the acetylation of non-histone proteins [10]. Over the past decade HDACs have attracted much attention as promising targets for therapeutic interventions in numerous malignancies, including prostate cancer.

HATs and HDACs can modify non-histone proteins such as AR as well as many other nuclear receptors and transcription factors such as p53. These modifications further influence transcriptional activity by altering protein-protein interactions, DNA binding affinity and protein stability [22]. HDAC activity is an important component of epigenetic silencing by DNA methylation and DNA methyltranferases. DNA methyltranferases have the ability to recruit HDACs which results in deacetylation of histones and repression of transcription. Methyl binding proteins also play a role in recruiting HDACs.

There are four classes of HDACs (I-IV), displayed in table 2. HDAC classes I,II and IV are all zinc dependent deacetylases which can be inhibited by a broad spectrum HDAC inhibitors, such as suberoylanilide, hydroxamic acid (SAHA, Zolinza®, Vorinostat), trichostatin A (TSA), and LBH589 (Carew et al., 2008). Class III deacetylases are a large family of Sirtuins which are evolutionary distinct, with a large unique enzymatic mechanism dependent on the cofactor NAD⁺. This family of deacetylases are virtually unaffected by all HDAC inhibitors which have been explored to date (Drummond et al., 2005). Development of specific inhibitors of SIRT activity is an emerging field of investigation as their inhibition may produce promising anticancer effects.





1,2,3 and 8

Zinc dependent deacetylases

Ubiquitously expressed

Predominatly localized in Nucleus


4, 5, 7 and 9

Zinc dependent deacetylases

Tissue specific expression in nucleus and cytoplasm


6 and 10

Zinc dependent deacetylases

Tissue specific expression in nucleus and cytoplasm

III (Sirtuins)

SIRT-1, 2, 3, 4, 5, 6 and 7

Dependent on NAD⁺

Structurally not related to other HDACs

Ubiquitous expression

Subcellular localization differs between Sirtuins



Zinc dependent deacetylases

Tissue specific expression

Enriched in brain, heart, muscle, kidney and testis

Table 1: Histone deacetylase classes and their characteristics. Adapted from [9]


Histone deacetylase inhibitors are compounds which induce hyperacetylation, reactivate suppressed genes and have pleiotropic cellular effects which inhibit tumour cell growth and survival. There are seven different classes to which these HDAC inhibitor compounds can be classified. Classification is dependent upon chemical structure and their HDAC inhibiting functions; cell growth arrest, differentiation and/or apoptosis. The seven classes are; short chain fatty acids, hydroxamate compounds, cyclic tetrapeptides, benzamides, trifluoromethylketones, hydroxamate-tethered phenylbutyrate derivatives and finally a miscellaneous category.

The short chain fatty acid class of HDAC inhibitors consists of butyrate and valproic acid, with activity at milimolar concentrations, a characteristic that may limit their use in the clinic [21]. Valproic acid inhibits growth of prostate cancer cells in vitro and reduces tumour xenograft growth in athymic nude mice owing to inhibition of histone acetylation by HDAC1 [23, 24].

The hydroxamate compounds class of HDAC inhibitors consists of trichostatin and syntheteic compounds vorinostat and panobinostat. These compounds work at low micromolar or nonomolar concentrations by binding to the catalytic site of the enzyme (Bolden et al., 2007; Butler at al., 2000). Vorinostat was the first HDAC inhibitor to be approved by the Food and Drug Administration. It is a pan-inhibitor of class I and class II HDAC proteins (Marks et al., 2007). Vorinostat and panobinostat both induce cell death and inhibit growth in prostate cancer cell lines through AR expression inhibition (Rakhlin et al., 2006; Marrocco et al., 2007). Vorinostat was also shown to supress tumour growth and decrease size in mice transplanted with CWR22 human prostate tumour cells, with little adverse effects [25].

The cyclic tetrapeptides class of HDAC inhibitors consists of romidepsin, trapoxinA and apicidin. Romidepsin induces cell death and inhibits cell proliferation by arresting cell cycle transition at the G1 and G2/M phases at nonomolar concentrations [26].

The benzamide class of HDAC inhibitors comprises of a diverse range of synthetic agents such as entinostat and tacedinaline. These compounds have potency at micromolar concentrations [21]. Qian and colleagues investigated the anti-tumour effects of entinostat on prostate cancer models, revealing that entinostat arrests the growth of PC-3 and LNCaP cells in vitro, induces cell death in DU145 cells and inhibits the growth of subcutaneous tumour xenografts of these three cell lines in vivo [27]. Molecular analysis illustrated increased H3 acetylation and p21 expression in patients treated with entinostat. Their study also illustrated that long term treatment with entinostat in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model slowed tumour progression and reduced cell proliferation [27].

The trifluoromethylketone and the hydroxamate-tethered phenylbutyrate derivatives classes of HDAC inhibitors require nanomolar concentrations in order to inhibit HDAC activity [21]. These classes and the miscellaneous HDAC inhibitors currently have no published data in relation to prostate cancer.


There are two major mechanism by which histone deacetylases induce apoptosis; extrinsic and intrinsic. The extrinsic pathway is mediated by a death receptor and the intrinsic pathway is also known as the mitochondrial mechanism of cell death.

One of the most promising properties of HDAC inhibitors is their ability to selectively induce apoptosis in malignant cells while sparing the normal cells. A possible reason for this may be due to the extrinsic pathway. The death receptor pathway is initiated when a FAS or Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) ligand binds to their death receptors. The binding of the ligand and death receptor leads to the recruitment of the adaptor protein FADD and caspase-8 activation.

When chemotherapeutic drugs are administered, they induce a stress on the cell which disrupts the mitochondrial membrane, initiating the intrinsic pathway and resulting in the release of proteins. The release of cytochrome c leads to the formation of the apoptosome and activation of caspase-9. Caspase-8 and caspase-9 can then cleave caspase-3, 6 and 7, resulting in apoptosis. HDAC inhibitors can induced pro-apoptotic (Bax, Bak, Bim and Bid) genes and inhibit ant-apoptotic (Bcl-2, Bcl-X, Mcl-1) genes, thus shifting the intrinsic pathway to cell death. However, Bcl-2 and Bcl-X have been shown to block HDAC inhibitor mediated apoptosis (Rosato et al., 2003; Zhang et al., 2004). BH3-only proteins may play a role in initiating apoptosis; Bmf and Bim are both transcriptionally activated and Bim is cleaved in response to inhibition of HDAC activity (Zhang et al., 2004; Zhang et al., 2006). HDAC inhibitors can stimulate apoptosis independent of p53, however, p53 mediated apoptosis has been reported upon treatment with certain classes of HDAC inhibitors.

Studies have reported that Vorinostat as well as other HDAC inhibitors have anti-angiogenesis properties, contributing to HDAC inhibitor anti-cancer effects. Tumours are dependent on angiogenesis for their nutrient supply, and for metastatic spread. Thus the suppression of pro-angiogenic factors such as VEGF and HIF1α benefit the HDAC inhibitor [28, 29].

Chen and colleagues reported that histone deacetylation inhibitors (Trichostatin A, Suberoylanilide hydroxamic acid, MS-275 and OSU-HDAC42) sensitized prostate cancer cells to DNA damaging agents targeting Ku70 acetylation. Ku70 is a vital compartment of the non-homologous end joining repair machinery for DNA double strand breaks, thus hyperacetylation of Ku70 reduces its ability to repair drug-induced DNA damage which in turn sensitizes cancer cells to agents which induce double strand breaks. This characteristic of HDAC inhibitors sensitizing cancer cells through alterations to the Ku70 acetylation opens up a novel route for combination therapy to improve outcome [30].


Vorinostat was licenced by the FDA in October 2006 for the treatment of cutaneous T cell Lymphoma (CTCL). Romidepsin was also approved for CTCL in November 2009. There are currently 12 different HDAC inhibitors in some phase of clinical trial as monotherapy or combination therapy with chemo, radio or hormone therapy, in a variety of cancers. There are a number of HDAC inhibitors in relation to prostate cancer listed on the clinicaltrials.gov website which are currently under investigation. There is ample research into the field of HDAC inhibitors which can be seen in the amount of on-going clinical trials.










Prostatic neoplasm








Prostate Adenocarcinoma




Prostate Cancer




Prostate Cancer




Prostate Cancer




Prostate Cancer




Prostate Cancer




mProstate Cancer




Prostate Cancer



Table 2: A summary of the drugs, cancers and phases of HDAC inhibitors on the clinicaltrials.gov website.


Recent studies have highlighted the importance of methylation of lysine (K) and arginine(R) residues in histone tails with respect to transcription. These residues are subject to monomethylation (me1), dimethylation (me2) and trimethylation (me3). Whether methylation leads to transcriptional activation or repression is dependent upon the site and extent of methylation. Methylation of H3K9, H3K27 or H4K20 are generally associated with gene silencing, whereas methylation of H3K4, H3K36 and H3K79 are related to active gene expression [31].

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Histone methylation on the chromatin structure is mediated by the recruitment of methylation specific binding proteins – histone methyltransferases. Four subgroups have been identified which are capable of binding to methylated lysine; chromodomain, Tudor domain, the WD40 repeats and the PHD domain. Methyltranferases can be ‘readers’ or ‘writers’ of the histone code as they may consist of more than one of these subgroups.


Histone Lysine methylation can be either active or repressive, depending on the histone tail residue it resides, allowing for specific modifications. The histone tails can be used as specific ‘markers’ of transcriptionally active or inactive chromatin. H3K4, H3K36 and H3K79 methylation is associated with ‘active’ transcription, whereas methylation of H3K9me2/3 H3K20me2 and H3K27me2/3 are related to ‘inactive’ or silenced transcribed chromatin [32] [33], . During histone modifications, one acetyl group is added to the lysine residue at a time, while up to three methyl groups per lysine may be present.

Mono/di-methylation of H3K9 can be located in silent regions in euchromatic genes, whereas trimethylation of H3K9 is enriched in pericentromeric heterchromatin suggesting that different methylation patterns mark distinct domains of heterchromatin [34].

There are three families of enzymes which are involved in lysine methylation; the PRMT family, the SET-domain family and the non-SET-domain family. The PRMT enzyme family methylate arginine residues while the SET-domain and non-SET-domain families both methylate lysine residues reviewed in [31].


Histone lysine methylation, like many other epigenetic modifications, is evolutionary conserved and reversible. Histone lysine demethylation is the most recently discovered family of ‘erasers’. Histone lysine demethylases abbreviated to KDMs are a novel family of histone modifiers which specifically remove methyl groups be mono, di or tri methyls from lysines on histones (H3K4me3/2/1, H3K9me3/2/1, H3K36me3/2/1 and H3K27me3/2) [35]. Shi and colleagues and Metzger and colleagues identified the first histone lysine-specific demethylase – lysine-specific demethylase 1 (LSD1/KDM1A) [36, 37]. Their discovery suggested a new insight into the regulation of chromatin dynamics and showed that active demethylation is linked to both activation and repression of transcription, and can ultimately behave as oncogenes or tumour suppressor genes depending upon cellular content.

Lysine specific demethylases have been given a more generic name which reflects their type of enzymatic function and the residue they modify. Thus lysine specific demethylases have are universally called KDMs (K-demethylases).

Through the action of lysine specific demethylation, KDMs play functional roles in cellular proliferation. Many studies have shown that amplifications and/or mutations of KDMs have been linked to histone methyl modifications and have also been linked to many types of cancer. The incidence of these amplifications and mutations of KDMs have been detected in many cancer types from haematological to solid neoplasms, including prostate cancer, oesophageal squamous cell carcinoma, desmoplastic medulloblastoma, metastatic lung sarcomatoid carcinoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and breast cancer. The full extent to exactly how KDMs function in cancer, its development and progression remains unclear, further research into the exact functions remains to be explored.

KDMs are grouped into two classes dependent upon their enzymatic activity; the flavin adenine dinucleotide (FAD) dependent KDM family and the Jumonji C (JmjC) KDM family (JDHMS). KDM1A can act as an oncogene or a tumour suppressor gene as it can activate gene transcription through H3K9 demethylation, while on the other hand repressing gene transcription through H3K4 demethylation. These characteristics are what give KDMs their double edged sword form. KDM1B (also known as LSD2) was the second KDM to be identified. It functions by demethyating H3K4me2/1 which results in repression of gene transcription.


KDM1 belongs to a family of FAD-dependent KDMs which can demethylate histones in a FAD-dependent oxidative reaction. During this process, FAD oxidises the methyl-lysine to lysine and formaldehyde [38]. KDM1 specifically demethylates mono or di-methylated H3K4me1/2 (Shi, 2004). KDM1 has two homologues A and B, which are both flavin dependent demethylases with the same histone residue [35]. As previously mentioned H3K4me2 is an active mark, thus KDM1 favours gene silencing. However, when KDM1 is recruited by androgen receptor (AR) in prostate cancer, KDM1A loses its ability to demethylate H3K4me1/2 which results in it catalysing the demethylation of H3K9me1/2, thus acting as a co-activator [39].

JDHM family are a much larger family of KDMs in comparison to FAD-dependent KDMs. JDHMs are able to tri-demethylate lysines as their active sites are large enough to occupy three methyl groups. For their reaction, JDHMs require Fe²âº and α-ketoglutrate in the presence of oxygen resulting in the conversation of methyl to hydroxymethyl releasing formaldehyde [38]. KDM2A was the first JDHM identified with H3K36 demethylation activity. The discovery of KDM2A was followed by the identification of many other KDM members and their homologues; KDM3- A, B, C, KDM4- A, B, C, KDM5- A, B, C, D, KDM6- A and B.

Each member of the JDHM family is characterized by one or more target histone residues. KDM2 and KDM5 clusters are involved in the removal of active marks such as H3K4me2 and H3K36 me2, resulting in gene silencing [40]. Whereas, KDM3 and KDM6 are involved in gene reactivation [41]. KDM3 genes with the aid of G9a, a putative oncogene, remove H3K9me2, a repressive mark. KDM6 removes polycomb dependent H3K27me3 which results in a possible tumour repressive function in prostate cancer [42]. KDM4 and its isoforms have both active and repressive enzymes [35].

It is no surprise that KDMs play functional roles as tumour suppressors or oncogenes considering there are so many members, each having more than two homologues, and exhibiting different functions.

KDM1 was the first identified KDM and as a result has been the most elucidated. Rotili and colleagues revealed that KMD1A is a putative oncogene in prostate cancer among other cancers [35]. The relationship between KDM1A and oncognesis partially resides on its ability to trigger MYC dependent transcription [43] while inhibiting p53 pro-apoptotic function [44]. P53 is a well characterised tumour suppressor gene which plays a functional role in numerous cancers in promoting cell death. Inhibition of p53 can have detrimental effects in carcinogenesis. KDM1 also has many other non-histone targets substrates such as DNMT1, STAT3, MYPT1 and E2F1.

KMD1A plays a vital role in the co-activation of AR in prostate cancer [45]. KDM1A in conjunction with AR switches its specificity for H3K4me1/2 to H3K9me1/2, thus resulting in a change from co-repressor to co-activator [46]. Interestingly, parglyine blocked demethylation of H3K9me1/2 during androgen-induced transcription [45], and the tranylcypromine derivatives NCL-1 and NCL-2 [47] reduced androgen dependent proliferation in prostate cancer cells through the inhibition of KDM1A.

KDM1A may also play a role as an AR co-repressor. KDM1 is recruited by AR, when androgen concentrations are elevated, to aid in the silencing of AR [48]. Elevated KDM1A expression in primary prostate cancer predicts an increased risk of relapse post prostatectomy [49]. Crea and colleagues suggest that the negative feedback loop of KDM1 and AR co-activation/repression is probably disrupted in CRPC as low androgen levels favours AR overexpression, and that KDM1A triggers androgen dependent proliferation and recurrence following therapy [50].

KDM4C cooperation with KDM1A in order to remove H3K9 methylation marks is too related to possibly activating AR targets [51]. Also, KMD4C has been reported to contribute to cancer cell proliferation [52], as well as showing higher expression in CRPC in comparison to hormone sensitive tumours and prostate hyperplasia.

PHF8 was identified as a novel oncogene in prostate cancer through a systematic knockdown of epigenetic enzymes conducted by Bjorkman and colleagues. It was overexpressed in cancerous prostate cells in comparison to a healthy prostate [53]. They discovered that PHF8 contributes to gene activation through the demethylation of H3K9me1/2, H3K27me2 and H4K20me1. PHF8 was also shown to be connected with high Gleason grade, prostate cancer invasion and metastasis, crucial characteristics of disease spread and poor prognosis. Inhibition of PFH8 was shown to reduce proliferation of AR positive and AR negative prostate cancer cells, which would suggest a positive target for prevention of prostate cancer progression.

Other studies have suggested that KDM5 and its homologues may also be involved in prostate cancer metastasis. Xiang and colleagues revealed that KDM5B is an AR co-activator and that it is up regulated in prostate cancer, both local and metastatic. KDM5C also plays a role in prostate cancer metastasis through the inhibition of transcriptional activity. It is proposed that KDM5C may function as an oncogene in early prostate cancer but hinder metastatic spread in lather stages.

KDM6B is a KDM specific to demethylation of H3K27 and is associated with high Gleason grade and poor prostate prognosis [54]. The trimethylation of H3K27 is mediated by the polycomb repressive complex component of EZH. EZH2 is a histone lysine methlytransferase generally associated with gene silencing. EZH2 is up regulated in metastatic prostate cells and plays a functional role in cell invasion and blood supply [50].

Table 1 displays a clear illustration of KDMs involved in prostate cancer and the role they are believed they carry out. Further evaluation of these KDMs may be needed in order to fully clarify their role in prostate cancer development, progression and metastasis as well as their relationship with AR. However, KDMs are a promising avenue for a novel targeted therapy in


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