Epigenetic Cancer Therapy: Rationales, Targets and Drugs
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Oncogene (2012) 31, 4257–4265 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc REVIEW Epigenetic cancer therapy: rationales, targets and drugs M Rius and F Lyko Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany The fundamental role of altered epigenetic modification many tumors show an aberrant epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory pattern. These tumor-specific epigenetic alterations or enzymes as important targets for cancer therapy. Over the epigenetic mutations, affect a variety of cancer-related past few years, several drugs with an epigenetic activity genes. The most prominent example for epimutations is have received approval for the treatment of cancer provided by the widely observed epigenetic silencing of patients, which has led to a detailed characterization of tumor suppressor genes that is closely associated with their modes of action. The results showed that both promoter hypermethylation (Esteller, 2007; Jones and established drug classes, the histone deacetylase (HDAC) Baylin, 2007). It has long been known that DNA inhibitors and the DNA methyltransferase inhibitors, show methyltransferase inhibitors can effectively induce DNA substantial limitations in their epigenetic specificity. HDAC demethylation and phenotypic changes related to the inhibitors are highly specific drugs, but the enzymes have a reactivation of epigenetically silenced genes (Jones and broad substrate specificity and deacetylate numerous Taylor, 1980). These findings were later adapted to the proteins that are not associated with epigenetic regulation. targeting of epigenetic mutations in cancer and thus Similarly, the induction of global DNA demethylation by established the fundamental concept of epigenetic non-specific inhibition of DNA methyltransferases shows cancer therapy (Egger et al., 2004). pleiotropic effects on epigenetic regulation with no apparent Research over the past decade has shown that tumor-specificity. Second-generation azanucleoside drugs epigenetic regulation occurs on several mechanistic have integrated the knowledge about the cellular uptake and levels, including DNA methylation, covalent histone metabolization pathways, but do not show any increased modifications and small regulatory RNAs (Esteller, specificity for cancer epigenotypes. As such, the traditional 2007; Jones and Baylin, 2007). Thus, in addition to rationale of epigenetic cancer therapy appears to be in need DNA methyltransferase (DNMT) inhibitors, histone of refinement, as we move from the global inhibition of deacetylase (HDAC) inhibitors have also contributed to epigenetic modifications toward the identification and shape epigenetic cancer therapy. Altogether, there are targeting of tumor-specific epigenetic programs. Recent currently four FDA-approved drugs with an epigenetic studies have identified epigenetic mechanisms that promote mode of action: the DNA methyltransferase inhibitors self-renewal and developmental plasticity in cancer cells. 5-azacytidine (Vidaza) and decitabine (20-deoxy-5-aza- Druggable somatic mutations in the corresponding epige- cytidine, Dacogen) and the HDAC inhibitors suberoy- netic regulators are beginning to be identified and should lanilide hydroxamic acid (SAHA, Zolinza) and facilitate the development of epigenetic therapy approaches romidepsin (Istodax). Various additional DNMT and with improved tumor specificity. HDAC inhibitors are currently being evaluated in Oncogene (2012) 31, 4257–4265; doi:10.1038/onc.2011.601; preclinical studies and in clinical trials. However, there published online 19 December 2011 are currently no clinical trials with drug candidates directed against other epigenetic targets. This situation Keywords: DNA methylation; chromatin; DNA methyl- warrants a detailed discussion of DNMT and HDAC transferase inhibitors; histone deacetylase inhibitors; inhibitors before novel approaches towards an epigenetic metabolic activation; stem cells therapy of cancer are considered. 5-Azacytidine and decitabine have shown significant clinical benefit in the treatment of myelodysplastic syndrome (Silverman et al., 2002; Kantarjian et al., 2006) and are also used for the treatment of myeloid Introduction leukemias. Both drugs are particularly effective when administered at low doses, which are sometimes below The traditional rationale for the development of 10% of their maximum tolerated doses (Issa and epigenetic cancer drugs is based on the observation that Kantarjian, 2009). These conditions are generally assumed to maximize DNA demethylation responses, and several studies have confirmed that drug-induced Correspondence: Dr F Lyko, Deutsches Krebsforschungszentrum, Im DNA demethylation occurs in patients (Issa et al., 2005; Neuenheimer Feld 580, 69120 Heidelberg, Germany. Mund et al., 2005; Soriano et al., 2007; Stresemann and E-mail: [email protected] Received 14 September 2011; revised and accepted 21 November 2011; Lyko, 2008). However, a direct link between DNA published online 19 December 2011 demethylation and clinical responses has not been Epigenetic cancer therapy M Rius and F Lyko 4258 demonstrated yet and there are currently no established required the presence of HR23B. These data suggest DNA methylation biomarkers that accurately predict that HDAC inhibitors target aberrant proteasome patient responses (Fandy et al., 2009). This remains as activity in cancer cells, which is possibly mediated by an important challenge that is related to the complex hyperacetylation of proteasome-associated non-histone mode of action of azanucleosides (see below) and that proteins. will have to be addressed in future studies to firmly Moreover, when yeast cells were incubated in the establish clinical proof-of-concept for epigenetic therapy presence of the HDAC inhibitor valproic acid, the drug with these drugs. specifically counteracted the activation of the ATR- The HDAC inhibitors SAHA and romidepsin are mediated DNA damage checkpoint response (Robert approved for the treatment of cutaneous T-cell lympho- et al., 2011). Surprisingly, the effect on DNA damage ma (Olsen et al., 2007; Piekarz et al., 2009). Numerous repair involved the degradation of key recombination additional HDAC inhibitors are currently undergoing proteins by autophagy (Robert et al., 2011). These clinical testing. The high number of developmental observations were explained by a model where protein drugs is related to the excellent druggability of the acetylation marks DNA recombination proteins for HDAC enzyme family, which permits the development transport to the vacuole and subsequent degradation, of potent isoenzyme-specific inhibitors (Bolden et al., and where deacetylation of these factors is required for 2006). It is important to notice that histone deacetyla- their stabilization in subnuclear compartments with tion has been shown to synergistically interact with severely damaged DNA. In this model, HDAC inhibi- DNA methylation in the epigenetic silencing of cancer tors would affect major oncological pathways (DNA genes (Cameron et al., 1999). This observation has also damage response and autophagy) without invoking any provided the scientific rationale for various clinical trials effects on epigenetic gene regulation. Altogether, these with combinations of DNMT and HDAC inhibitors. findings further illustrate why HDAC inhibitors should Somewhat surprisingly, these studies have yet to reveal not be considered as specific epigenetic drugs. It is synergistic clinical effects, which might again be related possible (although not proven) that targeting of other to complexities in the drugs’ modes of action that are histone modifying enzymes, like histone methyltrans- only beginning to become elucidated (see below). ferases and histone demethylases, might permit a higher degree of epigenetic specificity (see below). Are HDAC inhibitors epigenetic drugs? Epigenetic cancer therapy with DNMT inhibitors The important role of HDAC inhibitors in current concepts of epigenetic cancer therapy is often inter- The most frequently used epigenetic drugs are the preted to reflect a high specificity of HDACs for histone cytosine derivatives 5-azacytidine and decitabine. Both substrates. However, similar to the situation with DNA drugs are undergoing a series of metabolic activation methyltransferase inhibitors, a direct link between drug- steps before they can become incorporated into nucleic induced histone hyperacetylation and clinical responses acids (Figure 1). Incorporation of azacytosine bases into remains to be established. It is now becoming increas- DNA and RNA triggers a multitude of stress and ingly clear that the enzymatic activity of HDACs is not damage signaling pathways (Hollenbach et al., 2010), restricted to histone proteins, and treatment of human but also induces the formation of covalent adducts cancer cell lines with highly specific HDAC inhibitors between DNA and DNA methyltransferases. This can induce hyperacetylation of 1750 proteins (Choudh- covalent trapping results in the depletion of the enzymes ary et al., 2009). This finding strongly suggests that non- and thus causes a global reduction of DNA methylation histone proteins constitute the large majority of HDAC (Stresemann and Lyko, 2008). A global reduction of substrates. In addition, these studies also suggest that DNA methylation has been shown to have antitumoral the complexity and functional significance of the human effects in a mouse model for intestinal tumorigenesis