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WHAT IS EPIGENETICS? In the early 1940s, C. H. Waddington coined the term epigenetics to mean “above or in addition to genetics” “genome information that is superimposed on the DNA sequence” How can identical twins have different hair colors? How do different adult stem cells know their fate? Myoblasts can only form muscle cells Keratinocytes only form skin cells Hematopoetic cells only become blood cells But all have identical DNA sequences. 2 Modern definition is non-sequence dependent inheritance. Epigenetic phenomena are reversible Epigenetic phenomena are critical for the embryonic development, aging, and the process of many diseases including cancers. A bridge that connects environmental factors to our genes and bring the phenotype into being. 3 EPIGENETIC MECHANISMS RNA Interference Gene Expression Histone Modifications DNA Methylation 4 DNA METHYLATION DNA methylation is a unique modification of DNA and the most common epigenetic phenomenon in eukaryotic cells. DNA methyltransferases catalyze the transfer of methyl group from S-adenosylmethionine (AdoMet) to the carbon-5’ position of cytosine in CpG dinucleotides. 5 HISTONE MODIFICATION When histones are tagged, or acetylated, chromatin is open and genes are potentially active; When histones are not chemically tagged, deacetylated, the chromatin condenses and genes silenced. Levels of acetylation of the core histones result from the steady balance between HAT and HDAC. Active Inactive HDAC HAT 6 Non coding RNAs RNA which is not used for making proteins (non-coding RNA) can be cleaved and used to inhibit protein-coding RNAs siRNAs, microRNAs (~22 Nucleotides; fine tune gene Expression) 7 WHAT IS CANCER? Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. 8 Abnormal accumulation of abnormal cells with a loss of control to grow and spread Cell Proliferation Homeostasis Regulation of Cell Cycle: Cell Cycle Check points Cell Death Control of Apoptosis Cancer arises from both, epigenetic and genetic abnormalities, that cause deregulated gene expression and function Regulation by genetics involves a change in the DNA sequence, whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region 9 10 The human body is prone to developing cancer, from a very early stage of life, until the end of life The human genome has several built in tumour suppressor genes, whose protein products suppress the formation of tumours. It is important for these genes to continue expressing their tumour suppressor proteins as long as the person lives To date, more than 600 genes, including tumor suppressor genes, oncogenes, and cancer-associated viral genes, have been reported to be regulated by epigenetic mechanisms. For example, these genes include APC, ER, RAR, p15, p16, p73, DAPK1, E-cathedrin, GSTP1, LKB1, MGMT, TIMP3, and VHL 11 EPIGENETICS AND CANCER There is evidence that epigenetic deregulation can be a preliminary transforming event. Epigenetic changes such as global DNA hypomethylation and promoter-specific hypermethylation are commonly observed in early-stage tumors. This suggests that epigenetic alterations are early events in the loss of cellular homeostasis and may precede genetic mutations and genomic instability Deregulated epigenetic mechanisms may initiate genetic instability, resulting in the acquisition of genetic mutations that inactivate tumor-suppressor genes and activate oncogenes The most frequent epigenetic changes are increased methylation of CpG (phopshorylated cytosine-guanine) islands within gene promoters and deacetylation or methylation of histones 12 DNA METHYLATION AND CANCER 13 Robertson, Nature Reviews Genetics, Vol6, 597 PROGRESSIVE CHANGES IN PROMOTER METHYLATION AT CPG SITES DURING CANCER INITIATION AND PROGRESSION 14 THE POSSIBLE ROLE OF DNA METHYLATION IN CARCINOGENESIS Mechanism Initiation & early progression Mutation Epigenetic gatekeeper gene silencing Activation of normally silenced allele by loss of imprinting Activation of oncogene and chromosomal instability Interrelationship with histone modifications Inactivation of repair gene Spontaneous deamination at methylcytosine residue Cancer progression Epigenetic plasticity Spreading of aberrant methylation Metastasis Epigenetic plasticity 15 HISTONE MODIFICATIONS AND CANCER Acetylation and methylation of lysine-rich histone tails are two major post-translational modifications involved in the regulation of chromatin structure and gene expression. Alteration of histone modification profiles causing TSG silencing is associated to carcinogenesis 16 Genetic Mutations in Epigenetic Modifiers in Cancer 17 Epigenetic alterations are reversible, unlike genetic ones and occur at the earliest steps of carcinogenesis, placing epigenetic drugs at the forefront of cancer therapy and represent opportunities not only for therapeutic but also for preventive interventions “Epi-drugs", which are drugs targeting epigenetic mechanisms, show promise in cancer therapy. Natural products modulating epigenetic mechanisms constitute part of the hope offered by pharmacoepigenomics in cancer prevention and treatment 18 PLANT-DERIVED ANTICANCER DRUGS WITH EPIGENETIC ACTIVITIES Plant-derived anticancer drugs with epigenetic tumor inhibitory mechanisms are divided into major minor groups based on the number of publications and the variety of targeted cancers. 19 Major plant-derived anticancer drugs as epigenetic modulators POLY-PHENOLS Polyphenols are plant secondary metabolites consisting of one or more (poly-) phenol unit(s). Their conjugated systems, and hence, electron delocalization properties enable them to efficiently quench free radicals. Additionally, phenols bear several hydroxyl groups making them excellent hydrogen bond donors which bind with high affinity to proteins and nucleic acids. Flavonoids are the largest and best characterized polyphenols and include the flavonols, flavones, catechins, flavanones, anthocyanidins, and isoflavonoids. Several polyphenolics mediate their anticancer activities by modulating the acetylation pattern of crucial genes and inhibiting hypermethylation of tumor suppressor genes, which is a landmark in cancer development 20 Anacardic acids are plant phenols extracted from traditional medicinal plants predominantly belonging to the Anacardiaceae family and have been shown to exhibit antitumor and anti-oxidant activity. Anacardic acid and analogues, such as benzamide derivatives, act as epigenetic modulators by inhibiting the HATs, p300, PCAF, and TBP interacting protein (TIP60) in cervical, breast, kidney, and prostate cancer cells and in lymphoid and myeloid leukemia cells OH O OH R 21 Curcumin or diferuloylmethane is a naturally occurring flavonoid derived from the rhizome of Curcuma longa (Turmeric). Curcumin epigenetically inhibits cancer through modulation of histone acetylation by altering the activities of both, HATs and HDACs. Curcumin induces HDAC1 and HDAC2 or inhibits HAT activity leading to a decrease in global and in H3 and H4 histone acetylation in prostate, liver, brain, and lymphoid leukemia cancer cells O H3CO HO OH OCH 3 OH 22 ALKALOIDS Alkaloids are naturally occurring compounds containing basic nitrogen atoms. CH 3 O NH N CH3 H2N Procainamide shows promising anticancer properties particularly through epigenetic modulation of DNA methylation. It inhibits DNMT activity in myeloid leukemia cells and specifically DNMT1 in colon cancer cells. DNMT1’s affinity to its two substrates, hemimethylated DNA and SAM, was decreased by procainamide through partial competitive inhibition. The inhibition of DNMT activity by procainamide leads to decreased promoter methylation of several genes, thus, 23 inducing their expression. TERPENOIDS Terpenes are hydrocarbons derived from fivecarbon isoprene units they can be modified to terpenoids through addition of oxygen atoms or skeletal rearrangements. Parthenolide, a 15-carbon terpenoid (sesquiterpene lactone), is commonly extracted from the European feverfew herb (Tanacetum parthenium) that specifically depletes HDAC1 proteins. Parthenolide also inhibits DNMT1 in lymphoid and myeloid leukemias 24 Minor plant-derived anticancer drugs as epigenetic modulators Other plant-derived anticancer drugs have shown promise as epigenetic modulators but were classified as minor compounds as their epigenetic mechanisms are less established than the previously described major ones Biochanin A and Daidzein from Glycine max (Soybean) Caffeic Acid and Chlorogenic Acid from Coffea arabica (Coffee) Catechin and Epicatechin from Uncaria rhynchophylla (Cat's claw herb) Thymoquinone from Nigella sativa (Black seed) 25 Examples of Plant derived epigenetic modulators for cancer treatment Compound Source Molecular targets Anti-caner properties 3,3′Diindolylmethane Digestive product of indole-3carbinol found in cruciferous vegetables inhibitory effect on decrease of proliferation HDAC activity by and promotion of tumor inducing proteasome- cell death mediated downregulation of several HDAC iso-enzymes Butyrate and its derivatives generated during gut flora-mediated fermentation of dietary fibers Inhibit HDAC activity, cell cycle arrest, induce DNA inhibition of proliferation, demethylation inflammation and oxidative stress, modulation of detoxification potential, and induction of differentiation and apoptotic cell death Compound Source Molecular targets Anti-caner properties Naturally occurring flavonoid derived from the rhizome of Curcuma longa decrease DNA methylation, decreases HAT activities and histone acetylation or reduces the expression of several HDAC isoenzymes accompanied by increased histone acetylation Anti-oxidant, antiangiogenic, antiproliferative and pro-apoptotic activities (−)polyphenol of green DNA demethylating Epigallocatec tea agent by inhibiting hin-3-gallate DNMT1 and to decrease promoter methylation of various TSGs leading to gene reactivation anti-oxidant, anti-proliferative, anti-invasive, antiangiogenic and pro-apoptotic effects Curcumin 27 Compound Source Molecular targets Anti-caner properties Genistein and daidzein polyphenols found inhibit DNMT1 activity, in soybean decrease methylation of promoter methylation of TSGs, induce histone acetylation by inhibiting HDACs and activating HATs Inhibit oxidative stress,angiogenesis, modulation of cell cycle regulation, and induction of apoptosis Quercetin polyphenol largely Decrease DNMT Inhibit present in the plant activity leading to p16 stress kingdom promoter demethylation and gene reactivation oxidative 28 Compound Source Molecular targets Anti-caner properties Resveratrol polyphenol found in grape and grape products such as red wine reduces DNMT1 expression and methylation of RARβ and PTEN genes inhibition of cell proliferation, induction of antiangiogenic response, and increased rate of apoptosis Sulforaphane isothiocyanate found cruciferous vegetables HDACi increasing in total and promoterspecific histone acetylation in cancer cells Decreased proliferation induction apoptosis and of 29 PLANT EXTRACTS WITH ANTICANCER AND EPIGENETIC ACTIVITES Polyphenols possess potent anti-oxidant and anticancer properties. Recently, polyphenol rich plant extracts have shown epigenetic activities in a variety of cancer types by modulating promoter methylation of critical tumor genes. Green tea rich polyphenol extract was found to decrease CDX2 and p16 promoter methylation in colon and gastric cancer cells, as well as in primary gastric carcinoma cells The Japanese rose (Rosa rugosa), allspice (Pimenta dioica) and pineapple guava (Feijoa sellowiana) crude extracts were shown to modulate histone acetylation in prostate cancer cells. 30 Most of the major plant-derived compounds are in cancer clinical trials, namely, curcumin, which entered Phase III. Among the minor plant-derived compounds, lycopene and thymoquinone are in cancer clinical trials Many epidemiological studies and research data suggest that a diet rich in fruit and vegetables may reduce cancer incidence by mediating multiple biological activities and conferring the ability to counteract cell signaling cascades and mechanisms leading to genotoxic damage, redox imbalances and other forms of stresses associated or leading to a deregulation of cellular homeostasis 31 CRITICAL ASSESSMENT During decades, the best way to fight against cancer was to destroy pathologically altered cells with cytotoxic anti-neoplastic drugs, which is still the standardized regimen for chemotherapy. However, it is now considered that chemoprevention, the use of natural dietary agents and/or synthetic compounds in healthy individuals without signs of malignancy, may represent a better chance to avoid the burden of cancer by delaying, preventing, or even reversing the development of tumor cells 32 CONCLUSIONS Many plant-derived compounds have been identified for their anti-cancer properties with an emerging field regarding the modulation of epigenetic events. Most compounds are evaluated regarding histone modifications (mainly acetylation) and DNA methylation 33 FUTURE DIRECTIONS We need to consider the long-term and eventually transgenerational effects of sustained preventive interventions. Furthermore, there is the necessity to identify biomarkers to monitor the efficiency of preventive interventions by epigenetic modulators and eventually to predict the need of such interventions, which is going towards a personalized medical approach. 34 REFERENCE SCHNEKENBURGER, M., M. DICATO AND M. DIEDERICH. 2014. PLANT-DERIVED EPIGENETIC MODULATORS FOR CANCER TREATMENT AND PREVENTION. BIOTECHNOLOGY ADVANCES, 32: 1123–1132. 35 THANKS