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Journal of Integrative Oncology
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Multi-Layered Epigenetic Regulatory Mechanisms Mediate Epithelial to Mesenchymal Transition in Cancer

Tara Boulding, Fan Wu, Anjum Zafar and Sudha Rao*

Biomedical Sciences, Faculty of Education, Science, Technology & Mathematics, University of Canberra, ACT 2617, Australia

*Corresponding Author:
Sudha Rao
Biomedical Sciences
Faculty of Education, Science
Technology & Mathematics
University of Canberra, ACT 2617, Australia
Tel: 61262015111
E-mail: [email protected]

Received date: November 27, 2014; Accepted date: December 06, 2014; Published date: December 15, 2015

Citation: Boulding T, Wu F, Zafar A, Rao S (2015) Multi-Layered Epigenetic Regulatory Mechanisms Mediate Epithelial to Mesenchymal Transition in Cancer. J Integr Oncol 4:127. doi:10.4172/2329-6771.1000127

Copyright: © 2015 Boulding, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Epithelial to Mesenchymal Transition (EMT) is a central feature of embryonic development and is also a critical early event in cancer progression and metastasis. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modifications, which form epigenetic signatures that mark active or inactive genes. These signatures are dynamically added or removed by a wide variety of histonemodifying epigenetic enzymes, which more recently have been found to include chromatin-associated signalling kinases. Here, we discuss the multi-layered regulation of gene transcription during EMT in cancer. Given that epigenetics-based therapeutics are showing promise for the treatment of cancer, unravelling the detail of these epigenetic signatures during EMT is crucial to the development of novel therapeutic strategies that exploit these mechanisms.


Epithelial to Mesenchymal Transition (EMT) is a central feature of embryonic development and is also a critical early event in cancer progression and metastasis. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modifications, which form epigenetic signatures that mark active or inactive genes. These signatures are dynamically added or removed by a wide variety of histone-modifying epigenetic enzymes, which more recently have been found to include chromatin-associated signalling kinases. Here, we discuss the multi-layered regulation of gene transcription during EMT in cancer. Given that epigenetics-based therapeutics are showing promise for the treatment of cancer, unravelling the detail of these epigenetic signatures during EMT is crucial to the development of novel therapeutic strategies that exploit these mechanisms.


Epithelial to Mesenchymal Transition (EMT); epigenetics; transcription; E-cadherin; cancer metastasis; histone modifications; signalling kinases

EMT is a key step in cancer progression and metastasis

Epithelial to Mesenchymal Transition (EMT) is a process of dynamic and reversible phenotypic switching. EMT is essential for driving plasticity in embryonic development and, importantly, in cancer progression (Figure 1) [1-3]. During EMT, differentiated neoplastic epithelial cells lose cell-cell adhesion and apical-basal polarity while acquiring a mesenchymal phenotype; specifically, cells gain motility and migration capabilities, become resistant to apoptosis, and exhibit increased invasiveness [4-7]. Neoplastic cells have inherent flexibility to exist in multiple states ranging from a fully differentiated epithelial state to a fully dedifferentiated mesenchymal state [4,8,9]. This phenotypic spectrum of cellular plasticity is largely attributed to multiple rounds of EMT and its opposite process mesenchymal to epithelial transition (MET) [10].


Figure 1:EMT is involved in cancer metastasis. Neoplastic epithelial cells can undergo epithelial to Mesenchymal Transition (EMT) during early stages of metastasis. EMT enables migration and intravasation of tumour cells, allowing their passive transport to distal locations in the body. At secondary sites, extravasation followed by mesenchymal to epithelial transition (MET) generates new tumours.

Physiological activation of EMT can be triggered by paracrine and autocrine EMT-inducing growth factors that activate downstream intracellular signalling cascades [4,11,12]. It is thought that the absence of such signalling can cause MET; thus, continuous signalling is essential for maintaining the mesenchymal characteristics of cells undergoing EMT [12,13]. Numerous growth factors such as transforming growth factor-beta (TGF-β), fibroblast growth factor (FGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) can induce EMT by triggering a number of different signalling pathways including TGF-β, Wnt, and Notch [11,14-18]. Combinatorial activation of these signalling pathways results in the activation of several EMT-inducing transcription factors (EMT-TFs) such as Snail, Slug, ZEB-1, ZEB-2, Twist, and members of the NF-κB family [15,16,19-25]. EMT-TFs have been shown to cooperate at key EMT gene promoters as part of complex regulatory networks that regulate gene transcription to drive EMT progression [26].

Several studies have demonstrated the central and cooperative manner in which EMT-TFs regulate EMT. For example, Snail knockdown reduces cell migration and invasion and induces MET, while Snail over expression increases cell migration and invasion and induces EMT [27-29]. Similarly, Twist over expression upregulates mesenchymal markers, cell migration, and induces EMT [30]. Slug is also an essential mediator of Twist-induced EMT, and Twist expression can induce Snail and hence initiate EMT [31,32]. Importantly, a large number of the genes controlled by EMT-TFs encode functional proteins such as the inducible mesenchymal markers vimentin, fibronectin, and N-cadherin and repressible epithelial markers that include E-cadherin [33,34]. The expression of these markers is not mutually exclusive, since differentiated epithelial cells may undergo partial EMT and co-express both epithelial and mesenchymal markers (Figure 2). Perhaps the most studied change in EMT is the hallmark loss of E-cadherin expression. E-cadherin (encoded by CDH1) is an adherens junction protein and a key repressor of cellular metastasis [35]. Loss of E-cadherin expression in in vitro culture systems and in vivo mouse models initiates EMT and enhances tumour metastasis [36,37]. The multifaceted epigenetics-based regulation of CDH1 is discussed in detail below.


Figure 2: A distinct set of proteins mark epithelial, mesenchymal and partially transitioned cells. Epithelial to mesenchymal transition is a morphogenetic process where cells lose cell-cell contact and apical-basal polarity to acquire partial EMT status. Subsequently, cells gain more motility by restructuring epithelial actin architecture to achieve a full mesenchymal state. The expression of proteins dynamically changes during EMT and distinct markers define the phenotype of the cells. Cells express more E-cadherin, catenins and claudins in an epithelial state, and gradually lose the expression of these proteins while gaining more mesenchymal markers, including N-Cadherin, laminin, fibronectin and vimentin in a mesenchymal state.

Recently, microRNAs (miRNAs) have been established as important regulators of EMT. miRNAs are a class of short non-coding RNA molecules involved in the RNA interference machinery. They selectively bind to target messenger RNAs (mRNA), mostly in the 3′ untranslated region, to post-transcriptionally regulate mRNA expression [38,39]. Many miRNAs have been implicated in EMT regulation including the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429), miR-205, miR-34, and miR-21 [40-42]. These miRNAs have a close functional relationship with a number of EMT-TFs including ZEB-1, ZEB-2, Snail, and NF-κB [40,41,43,44]. The relationship between the miR-200 family and ZEB family members is particularly well established [40]. During TGF-β-induced EMT, ZEBs are activated and they repress the activity of miR-200 family members, which in turn represses ZEB activity and thus regulates EMT via a double-negative feedback loop [45,46]. Intriguingly, this miR-200/ZEB balance can consecutively switch cells between epithelial and mesenchymal states in both directions [47]. High miR-200/low ZEB expression is associated with the pure epithelial state, while low miR-200/high ZEB expression is associated with the pure mesenchymal state [48]. Intermediate miR-200/ZEB expression represents the hybridised, partial EMT phenotype [48].

Epigenetic modifications control gene expression

Eukaryotes utilise the chromatin landscape as an epigenetic template to regulate gene transcription. Dynamic changes in chromatin structure (chromatin remodelling) play a key role in regulating genome function [49-51]. Highly compacted chromatin structures are enriched in nucleosomes and are transcriptionally silent. In contrast, a net loss of nucleosomes from gene-specific regulatory regions increases chromatin accessibility, enables binding of transcriptional regulators, and initiates gene expression [52,53]. With respect to transcription, chromatin predominantly exists in two interchangeable states: transcriptionally silent heterochromatin or transcriptionally active euchromatin (Figure 3). Chromatin remodelling orchestrates a gene’s transcriptional state via a number of mechanisms: (1) post-translational modifications of histone proteins; (2) DNA methylation; (3) the actions of ATP-dependent chromatin-remodelling complexes; (4) exchange of canonical histones with one of the variant histones; and (5) the action of non-coding RNAs [54,55]. This review focuses on the multiple layers of epigenetic control that govern EMT regulation in cancer.


Figure 3:Model for the multi-layered transcriptional mechanisms that mediate induction of gene expression programs. In response to extracellular signaling cues, a distinct cohort of genes are induced in the mesenchymal state. At such gene loci, chromatin can be reconfigured to an accessible state via nucleosome repositioning/ eviction, histone variant exchange or DNA methylation and posttranscriptional modification of histones. Histone modifiers including histone acetyltransferases, histone methyltransferases, and histone kinases can modify the histone tails by mediating acetylation, methylation, and phosphorylation, respectively. Ultimately, this leads to the exposure of key transcription factor DNA recognition elements, the binding of the factors and the recruitment of the RNA polymerase II transcription machinery. Non-coding RNAs are capable of maintaining heterochromatin formation. ATP: adenosine triphosphate; ADP: adenosine diphosphate; Ac: acetylation; Me: methylation; P: phosphorylation; TF: transcription factor; R: arginine; K: lysine; T: threonine; S: serine.

Epigenetic signatures are mediated by dynamic epigenetic enzymes

Post-translational modifications (PTMs) of the amino tails of histones are thought to be particularly important modulators of gene expression, either by changing chromatin structure and/or by providing a ‘histone code’ that acts as a tag for the tethering of transcriptional regulators to the epigenetic template [56]. These histone tags have typically been ascribed to either gene activation or repression depending on their location. For example, the promoter regions of actively transcribed genes are commonly enriched in H3K4 acetylation and H3K4, H3K36, and H3K79 tri-methylation. In contrast, the promoter regions of repressed genes are commonly enriched in H3K9 and H3K27 tri-methylation [57-60]. However, it is becoming increasingly apparent that a single PTM does not dictate the transcriptional outcome. Instead, it has been suggested that chromatin needs to be considered a ‘composite domain’ in which modifications work simultaneously to regulate gene expression [61].

These dynamic and reversible PTMs are orchestrated by numerous histone-modifying enzymes that can write or erase the histone code peppered across gene loci. For example, histone acetylation is catalysed by histone acetyl transferases (HATs), which transfer an acetyl group to lysine residues on H3 and H4 [62,63]. Histone acetylation neutralises the basic charge of lysine, consequently destabilising higher order chromatin folding leading to transcription [64,65]. The opposing deacetylation is catalysed by histone deacetylases (HDACs), which remove acetyl groups and thus repress transcription [66]. Indeed, global loss of H4K19ac is a common hallmark in human cancers, indicating that HDACs are important in tumourigenesis [67]. Moreover, HDACs have been found to be over expressed in several different cancer types including breast, colorectal, gastric, prostate, and renal cancers [68-72]. HDACs have been shown to have an important regulatory role in EMT. For example, HDAC1 is required for TGF-β-induced EMT, while HDAC3 is required for hypoxia-induced EMT after interacting with WDR5 [73,74]. Increased HDAC expression is also associated with increased proliferation, differentiation, invasion, and metastasis [69,75,76].

Compared to histone acetylation, histone methylation is a multifaceted modification since it can occur on arginine and lysine residues and can both activate and repress transcription [77]. Moreover, lysine residues may be mono-, di-, or tri-methylated, and arginine residues may be mono- or di-methylated. Methylation increases the hydrophobicity of histone side chains, increasing their affinity for transcriptional activators or repressors depending on the modified amino acid residue [78]. Methylation of H3K4, H3K36, or H3K79 recruits proteins responsible for activating transcription, whereas methylation of H3K9, H3K27, or H4K20 recruits transcriptional repressors that subsequently block transcription [57]. Until recently, methylation was thought to be a static modification; however, it is now known that demethylation is catalysed by lysine-specific demethylases (LSD1 and LSD2) and Jumanji C (JmjC) domain-containing proteins [57,79-81]. Both demethylate mono- and di-methylated lysine residues on histone 3 and can activate and repress transcription [79,82-85]. Several lysine methyl transferases interact with EMT-TFs to promote EMT. For example, MMSET directly regulates Twist expression by triggering H3K36 tri-methylation on the TWIST1 promoter, thus regulating EMT [86]. Set8 can physically interact with Twist to mono-methylate H4K20 on epithelial gene promoters, consequently initiating EMT and increasing the invasiveness of breast cancer cells [87]. Similarly, G9a catalyses H3K9 di-methylation on epithelial gene promoters, subsequently repressing their expression in a TGF-β-induced EMT model [88]. Intriguingly, global loss of H4K20me3 is a hallmark of cancer, implicating demethylase activity in cancer regulation [67]. LSD1 expression is elevated in a number of different cancer types including bladder, lung, ovarian, and prostate cancers [82,89-92]. Moreover, LSD1 levels are significantly higher in early stage tumours indicating a possible role for LSD1 in the initiation of tumourigenesis [82]. A recent study demonstrated that LSD1 executes genome-wide epigenetic reprogramming of large organised heterochromatin K9-modifications (LOCKS) domains in a TGF-β-induced murine hepatocyte model of EMT; specifically, a genome-wide reduction in H3K9me2 and an increase in H3K4me2 and H3K36me3 [93]. Moreover, a global increase in H3K4me3 and a reduction in H3K27me3 leads to transcription of EMT-related genes in a ‘stepwise’ prostate cancer EMT cell model [94]. Similarly, Twist-induced EMT stimulates a large-scale increase in H3K4me2 and the bivalent H3K4me3/H3K27me3 marks [95]. Collectively, these modifications appear to be essential for epithelial dedifferentiation.

In addition to these histone modifications, direct methylation of DNA plays a key role in transcriptional silencing. DNA methylation occurs at the 5’ position of cytosine residues within CpG dinucleotides and is catalysed by DNA methyltransferase enzymes (DNMTs) [54,96]. The role of DNA methylation and DNMTs in cancer regulation is well characterised and has been reviewed elsewhere [97,98]. A recent study found an inverse correlation between promoter methylation and expression of the EMT-TFs Snail and Slug [99]. Intriguingly, one analysis showed that DNA methylation patterns remain largely unchanged in TGF-β-induced EMT [93]. However, another demonstrated increased hypomethylation of epithelial-specific methylation sites and increased hypermethylation of mesenchymal-specific methylation sites [100]. However, McDonald et al. treated cells with TGF-β for 36 hours while Ruike et al. treated cells for five days, and the discrepancy between these results might indicate that TGF-β treatment longer than 36 hours is required to mediate changes in DNA methylation.

Signalling kinases have emerged as a novel class of epigenetic enzymes in EMT

It is widely understood that protein kinases are key participants of the signal transduction cascades that relay information from the cell surface to the nucleus to modulate gene expression programs [101-103]. The co-ordinated action and activation of these proteins provides the exquisite control necessary for the initiation of specific transcription programs. Traditionally, the action of signaling kinases was thought to predominantly occur in the cytoplasm. However, pioneering studies in yeast have shown that signal transduction kinases translocate to the nucleus and stably associate with the promoter and transcribed regions of genes to regulate expression [104,105]. These chromatin-tethered kinases have been shown to have both a structural role as part of transcription complexes and an enzymatic role by phosphorylating their target proteins [105-108].

There is growing evidence in higher eukaryotes that signal transduction kinases can have distinct functions in the cytoplasm and nucleus. For example, two upstream kinases in the NF-κB pathway, IKK1 and NIK, shuttle between the cytoplasm and nucleus in resting cells to facilitate basal NF-κB transcriptional activity [109]. IKK-α was shown to have an alternative role as a histone kinase that directly phosphorylates H3S10 at NF-κB-responsive gene promoters [110,111]. The p38 Mitogen Activated Protein Kinase (MAPK) is another signalling kinase that is recruited to the chromatin of muscle-specific loci, where it targets the SWI-SNF chromatin remodelling complex [112]. These findings illustrate the more general role of signalling kinases as regulators of gene transcription in both higher and lower eukaryotic cells via two distinct mechanisms: (1) cytoplasmic signalling to the nucleus and (2) direct association with chromatin-bound transcription complexes at activated target genes in the nucleus. For example, the novel PKC family member, PKC-θ, functions as an epigenetic enzyme and directly regulates key EMT genes in breast cancer [25]. In addition, the conventional PKC isoform, PKC-β, also functions as an epigenetic enzyme by directly tethering to the epigenetic template and phosphorylating histone H3T6 residues and blocking demethylation in prostate cancer [113].

The NF-κB family member p65 and IKK-β have been shown to play a role in TNF-α-induced expression of Twist and subsequent initiation of EMT [114]. p38 MAPK also regulates TGF-β-induced EMT changes in pulmonary epithelial cells [115]. Similarly, PKC-α has been shown to be a central regulator of cells that have undergone an EMT program [116]. However, it remains to be determined whether these enzymes mediate their actions through epigenetic mechanisms. Crosstalk between signalling kinases and the epigenetic platform in the context of EMT is, therefore, an emerging and key research area.

E-cadherin: a paradigm for epigenetic regulation of EMT

Epigenetic control is highly complex and involves co-ordinated, multi-layered regulation. CDH1 is a model gene for analysing epigenetic regulation since it is necessary for maintaining epithelial structure and preventing EMT [35] (Figure 4). When CDH1 transcription is occurring in epithelial cells, the CDH1 promoter is enriched with the H3K4me2 euchromatin mark and the histone variant H2A. Z [117,118]. In contrast, CDH1 repression is accompanied by the H3K9me2, H4K20me1, and H3K27me3 heterochromatin marks and hypermethylation and eviction of H2A. Z on the CDH1 promoter [87,88,117,119,120].


Figure 4: E-cadherin expression is regulated by layers of epigenetic control in EMT. The regulation of the CDH1 gene involves multiple layers of epigenetic regulation. Extracellular signaling pathways including TGF-β, Wnt, and Notch activate EMTinducing transcription factors (EMT-TFs) such as Snail, Slug, Twist, and ZEB-1/2. The EMT-TFs recruit various co-repressors which cooperatively repress CDH1 transcription. The CDH1 promoter is flanked by repressive histone marks like H3K9me2, H3K27me3 and H4K20me1. DNMTs can be recruited to the CDH1 promoter to repress gene transcription. CDH1 repression is also accompanied by the loss of histone variant, H2A.Z. The activity of some EMT-TFs such as ZEB-1/2 is regulated through a negative feedback loop involving members of the miR-200 family.

After activation of EMT-related signalling pathways, the EMT-TFs Snail, Zeb-1, and Twist are activated [19]. Snail binds to the E-box region of the CDH1 promoter and recruits several chromatin-remodelling complexes including the Mi-2/nucleosome remodelling and deacetylase (NuRD) repressive complex and polycomb repressive complex 2 (PRC2). The NuRD complex contains a number of proteins including HDAC1, HDAC2, mSin3A, and LSD1 [121-123]. It catalyses the removal of di-methylated H3K4 and deacetylation of H3 and H4 [118,121]. PRC2 contains the PcG proteins EZH2 and SUZ12, which function together to catalyse H3K27 tri-methylation [13,119]. Mi-2/NuRD and PRC2 recruitment leads to E-cadherin downregulation. Moreover, Snail induces ZEB-1 expression, which, in a similar manner, binds to the E-box region of the CDH1 promoter and recruits chromatin-remodelling proteins such as BRG1, which consequently suppresses E-cadherin expression [124,125]. Likewise, Twist represses CDH1 transcription by recruiting other partners such as BMI1 and SET8. In complex, BMI1 recruits PRC2, catalysing H3K27 tri-methylation, while SET8 catalyses H4K20 mono-methylation on the CDH1 promoter [87,126]. Twist can also recruit the Mi-2NuRD complex to the CDH1 promoter to repress transcription [127].

As well as histone modifications, genome-wide profiling has identified hypermethylation of the CDH1 promoter as a transcriptional repressor [120,128]. Intriguingly, cell division cycle 6 (Cdc6) protein binding on the CDH1 promoter evicts H2A.Z, leading to E-cadherin repression [117].

Epigenetic therapy is emerging as an effective treatment for cancer

Global changes in the epigenetic landscape are a hallmark of cancer. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy. Inhibitors of histone-modifying enzymes have recently shown promise as cancer therapeutics, with several ‘epi-drugs’ approved for clinical use [129]. Thus, determining the molecular mechanisms underpinning EMT and, in particular, distinct mesenchymal phenotypes such as cancer stem cells (CSCs) will be critical for the development of novel therapeutic strategies that target EMT in cancers.

The main epigenetic drugs being used in cancer clinical trials are HDAC inhibitors (HDACIs). HDACIs display anti-cancer activity by inhibiting angiogenesis and causing cell-cycle arrest [130-132]. Additionally, they are anti-proliferative and have the ability to selectively target cancer cells [133]. Importantly, clinical studies have shown that HDACIs are generally well tolerated and thus may have a safety profile suitable for widespread clinical use [134]. The first epigenetic enzyme to be approved by the Food and Drug Administration (FDA) was the HDACI vorinostat (suberanilohydroxamic acid; SAHA), after two successful phase II clinical trials in patients with cutaneous T-cell lymphoma [135,136]. Recent clinical trials are now using vorinostat in combination regimens to enhance the clinical efficacy [137,138]. Other HDACIs such as panobinostat and belinostat have been tested as monotherapies and as part of combination therapies in clinical trials with promising results [139-141].

Several epigenetic inhibitors have been shown to be effective repressors of EMT, predominantly by upregulating E-cadherin. Treatment with the DNMT inhibitor 5-aza-2′-deoxycytidine (5-Aza-dC) blocks CDH1 hypermethylation, restores E-cadherin expression, and initiates morphological MET in numerous cancer types [142,143]. 5-Aza-dC treatment also increases E-cadherin expression and in vivo metastases of breast cancer cells in a SCID mouse xenograft model [144]. Similarly, treatment with the HDACI butyrate stimulates E-cadherin upregulation in colon and hepatocellular cancer cells, while the HDACIs vorinostat and TSA also capable of stimulating E-cadherin expression in endometrial carcinoma cells [145-147]. A recent report has shown that the HDACI entinostat causes MET by reversing E-cadherin repressionin breast cancer cells [148]. However, it is important to note that HDACIs have been shown to induce EMT in prostate adenocarcinoma, endometrial adenocarcinoma, and head and neck squamous cell carcinoma cells [149-151]. These findings highlight the need to understand the molecular mechanisms underpinning their targeted inhibition. Additionally, a recent study demonstrated the benefits of using epigenetic inhibitors in combination with chemoimmunotherapy; specifically, the DNMT inhibitor decitabine was used to enhance NY-ESO-1 vaccine-induced immunity in patients with relapsed epithelial ovarian cancer [152]. Intriguingly, a receptor tyrosine kinase small-molecule inhibitor, sorafenib, inhibits TGF-β-induced EMT by epigenetically regulating EMT-associated genes. Specifically, sorafenib reverses the histones modified during TGF-β-induced EMT [153].

It is now well known that EMT generates a subpopulation of CSCs that are capable of extensive proliferation and differentiation [154]. Thus, novel EMT-based epigenetic therapies should focus on targeting this important subpopulation of cells that gives rise to metastases and recurrent disease. As novel classes of chromatin-associated enzymes are discovered as key regulators of CSCs and EMT, increasing numbers of small-molecule inhibitors with therapeutic potential are becoming available, including LSD1 and PKC inhibitors. LSD1 inhibitors selectively inhibit proliferation of pluripotent teratocarcinoma, embryonic carcinoma, seminoma, and embryonic stem cells while sparing non-pluripotent cells [155]. A number of PKC inhibitors have emerged as novel drugs with the potential to be used as therapeutic agents against EMT and CSCs. GÓ§6976, a PKC-α inhibitor, abrogates upregulation of Snail and downregulation of claudins after hypoxia-induced EMT in pancreatic cancer cells [156]. Some small-molecule PKC-δ inhibitors inhibit proliferation of the CSC niche in breast, pancreatic, and prostate cancer cell lines and in a breast cancer mouse xenograft model [157]. Several other PKC-α inhibitors, including Ro-31-8220 and bisindolylmaleimide I, reduce CSC-enriched subpopulations and tumour initiation enriched by the CSC subset [116]. Similarly, aurothiomalate, a novel PKC-ι inhibitor, selectively targets the stem cell niche of bronchioalveolar cells in an anti-proliferative manner, indicating its potential in targeting CSCs [158]. Our recent findings that show PKC-θ directly tethers to chromatin and regulates inducible gene expression in PMA-induced EMT and CSCs, which is abrogated after treatment with a PKC-θ-specific inhibitor [25]. PKC-θ is another novel epigenetics-based therapeutic target that needs to be explored in the clinic [25].

Future Directions

Recent data have exemplified the key role of epigenetic regulatory mechanisms in EMT, a critical step in tumour metastasis and recurrent aggressive disease. Epigenetics-based therapeutics hold great promise in the field of cancer biology, but it will be essential to uncover the multi-layered epigenetic regulatory mechanisms that occur during EMT to expedite this therapeutic approach (Figure 3). Given that cancer is a highly heterogeneous disease, understanding the molecular wiring in specific cancer cell subsets such as CSCs, especially in poor prognosis cancers with limited therapeutic options (such as pancreatic and ovarian cancer), will also be necessary. This strategy will undoubtedly aid the development of new therapeutic strategies in many cancers in which current therapeutic options are limited.


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