1 2352 141 EPIGENETIC REGULATION OF NRF2/KEAP1 BY PHYTOCHEMICALS. EPIGENETICS HAS PROVIDED A NEW DIMENSION TO OUR UNDERSTANDING OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (HUMAN NRF2/KEAP1 AND MURINE NRF2/KEAP1) SIGNALING. UNLIKE THE GENETIC CHANGES AFFECTING DNA SEQUENCE, THE REVERSIBLE NATURE OF EPIGENETIC ALTERATIONS PROVIDES AN ATTRACTIVE AVENUE FOR CANCER INTERCEPTION. THUS, TARGETING EPIGENETIC MECHANISMS IN THE CORRESPONDING SIGNALING NETWORKS REPRESENTS AN ENTICING STRATEGY FOR THERAPEUTIC INTERVENTION WITH DIETARY PHYTOCHEMICALS ACTING AT TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. THIS REGULATION INVOLVES THE INTERPLAY OF HISTONE MODIFICATIONS AND DNA METHYLATION STATES IN THE HUMAN NFE2L2/KEAP1 AND MURINE NFE2L2/KEAP1 GENES, ACETYLATION OF LYSINE RESIDUES IN NRF2 AND NRF2, INTERACTION WITH BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) ACETYL "READER" PROTEINS, AND NON-CODING RNAS SUCH AS MICRORNA (MIRNA) AND LONG NON-CODING RNA (LNCRNA). PHYTOCHEMICALS DOCUMENTED TO MODULATE NRF2 SIGNALING ACT BY REVERSING HYPERMETHYLATED STATES IN THE CPG ISLANDS OF NFE2L2 OR NFE2L2, VIA THE INHIBITION OF DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), THROUGH THE INDUCTION OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES, OR BY INDUCING MIRNA TO TARGET THE 3'-UTR OF THE CORRESPONDING MRNA TRANSCRIPTS. TO DATE, FEWER THAN TWENTY PHYTOCHEMICALS HAVE BEEN REPORTED AS NRF2 EPIGENETIC MODIFIERS, INCLUDING CURCUMIN, SULFORAPHANE, RESVERATROL, RESERPINE, AND URSOLIC ACID. THIS OPENS AVENUES FOR EXPLORING ADDITIONAL DIETARY PHYTOCHEMICALS THAT REGULATE THE HUMAN EPIGENOME, AND THE POTENTIAL FOR NOVEL STRATEGIES TO TARGET NRF2 SIGNALING WITH A VIEW TO BENEFICIAL INTERCEPTION OF CANCER AND OTHER CHRONIC DISEASES. 2020 2 616 43 BIOACTIVE COMPOUNDS IN OXIDATIVE STRESS-MEDIATED DISEASES: TARGETING THE NRF2/ARE SIGNALING PATHWAY AND EPIGENETIC REGULATION. OXIDATIVE STRESS IS A PATHOLOGICAL CONDITION OCCURRING DUE TO AN IMBALANCE BETWEEN THE OXIDANTS AND ANTIOXIDANT DEFENSE SYSTEMS IN THE BODY. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2), ENCODED BY THE GENE NFE2L2, IS THE MASTER REGULATOR OF PHASE II ANTIOXIDANT ENZYMES THAT PROTECT AGAINST OXIDATIVE STRESS AND INFLAMMATION. NRF2/ARE SIGNALING HAS BEEN CONSIDERED AS A PROMISING TARGET AGAINST OXIDATIVE STRESS-MEDIATED DISEASES LIKE DIABETES, FIBROSIS, NEUROTOXICITY, AND CANCER. THE CONSUMPTION OF DIETARY PHYTOCHEMICALS ACTS AS AN EFFECTIVE MODULATOR OF NRF2/ARE IN VARIOUS ACUTE AND CHRONIC DISEASES. IN THE PRESENT REVIEW, WE DISCUSSED THE ROLE OF NRF2 IN DIABETES, ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), CANCER, AND ATHEROSCLEROSIS. ADDITIONALLY, WE DISCUSSED THE PHYTOCHEMICALS LIKE CURCUMIN, QUERCETIN, RESVERATROL, EPIGALLOCATECHIN GALLATE, APIGENIN, SULFORAPHANE, AND URSOLIC ACID THAT HAVE EFFECTIVELY MODIFIED NRF2 SIGNALING AND PREVENTED VARIOUS DISEASES IN BOTH IN VITRO AND IN VIVO MODELS. BASED ON THE LITERATURE, IT IS CLEAR THAT DIETARY PHYTOCHEMICALS CAN PREVENT DISEASES BY (1) BLOCKING OXIDATIVE STRESS-INHIBITING INFLAMMATORY MEDIATORS THROUGH INHIBITING KEAP1 OR ACTIVATING NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS IN THE NUCLEUS, INCLUDING HO-1, SOD, AND CAT; (2) REGULATING NRF2 SIGNALING BY VARIOUS KINASES LIKE GSK3BETA, PI3/AKT, AND MAPK; AND (3) MODIFYING EPIGENETIC MODULATION, SUCH AS METHYLATION, AT THE NRF2 PROMOTER REGION; HOWEVER, FURTHER INVESTIGATION INTO OTHER UPSTREAM SIGNALING MOLECULES LIKE NRF2 AND THE EFFECT OF PHYTOCHEMICALS ON THEM STILL NEED TO BE INVESTIGATED IN THE NEAR FUTURE. 2021 3 4427 42 MOLECULAR BASIS OF ELECTROPHILIC AND OXIDATIVE DEFENSE: PROMISES AND PERILS OF NRF2. INDUCTION OF DRUG-METABOLIZING ENZYMES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE)-DEPENDENT TRANSCRIPTION WAS INITIALLY IMPLICATED IN CHEMOPREVENTION AGAINST CANCER BY ANTIOXIDANTS. RECENT PROGRESS IN UNDERSTANDING THE BIOLOGY AND MECHANISM OF INDUCTION REVEALED A CRITICAL ROLE OF INDUCTION IN CELLULAR DEFENSE AGAINST ELECTROPHILIC AND OXIDATIVE STRESS. INDUCTION IS MEDIATED THROUGH A NOVEL SIGNALING PATHWAY VIA TWO REGULATORY PROTEINS, THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND THE KELCH-LIKE ERYTHROID CELL-DERIVED PROTEIN WITH CNC HOMOLOGY-ASSOCIATED PROTEIN 1 (KEAP1). NRF2 BINDS TO KEAP1 AT A TWO SITE-BINDING INTERFACE AND IS UBIQUITINATED BY THE KEAP1/CULLIN 3/RING BOX PROTEIN-1-UBIQUITIN LIGASE, RESULTING IN A RAPID TURNOVER OF NRF2 PROTEIN. ELECTROPHILES AND OXIDANTS MODIFY CRITICAL CYSTEINE THIOLS OF KEAP1 AND NRF2 TO INHIBIT NRF2 UBIQUITINATION, LEADING TO NRF2 ACTIVATION AND INDUCTION. INDUCTION INCREASES STRESS RESISTANCE CRITICAL FOR CELL SURVIVAL, BECAUSE KNOCKOUT OF NRF2 IN MICE INCREASED SUSCEPTIBILITY TO A VARIETY OF TOXICITY AND DISEASE PROCESSES. COLLATERAL TO DIVERSE FUNCTIONS OF NRF2, GENOME-WIDE SEARCH HAS LED TO THE IDENTIFICATION OF A PLETHORA OF ARE-DEPENDENT GENES REGULATED BY NRF2 IN AN INDUCER-, TISSUE-, AND DISEASE-DEPENDENT MANNER TO CONTROL DRUG METABOLISM, ANTIOXIDANT DEFENSE, STRESS RESPONSE, PROTEASOMAL DEGRADATION, AND CELL PROLIFERATION. THE PROTECTIVE NATURE OF NRF2 COULD ALSO BE HIJACKED IN A NUMBER OF PATHOLOGICAL CONDITIONS BY MEANS OF SOMATIC MUTATION, EPIGENETIC ALTERATION, AND ACCUMULATION OF DISRUPTOR PROTEINS, PROMOTING DRUG RESISTANCE IN CANCER AND PATHOLOGIC LIVER FEATURES IN AUTOPHAGY DEFICIENCY. THE REPERTOIRE OF ARE INDUCERS HAS EXPANDED ENORMOUSLY; THE THERAPEUTIC POTENTIAL OF THE INDUCERS HAS BEEN EXAMINED BEYOND CANCER PREVENTION. DEVELOPING POTENT AND SPECIFIC ARE INDUCERS AND NRF2 INHIBITORS HOLDS CERTAIN NEW PROMISE FOR THE PREVENTION AND THERAPY AGAINST CANCER, CHRONIC DISEASE, AND TOXICITY. 2012 4 1416 50 DIETARY POLYPHENOLS REMODEL DNA METHYLATION PATTERNS OF NRF2 IN CHRONIC DISEASE. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR CRUCIAL IN REGULATING CELLULAR HOMEOSTASIS AND APOPTOSIS. THE NRF2 GENE HAS BEEN IMPLICATED IN VARIOUS BIOLOGICAL ACTIVITIES, INCLUDING ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTICANCER PROPERTIES. NRF2 CAN BE REGULATED GENETICALLY AND EPIGENETICALLY AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND TRANSLATIONAL LEVELS. ALTHOUGH DNA METHYLATION IS ONE OF THE CRITICAL BIOLOGICAL PROCESSES VITAL FOR GENE EXPRESSION, SOMETIMES, ANOMALOUS METHYLATION PATTERNS RESULT IN THE DYSREGULATION OF GENES AND CONSEQUENT DISEASES AND DISORDERS. SEVERAL STUDIES HAVE REPORTED PROMOTER HYPERMETHYLATION DOWNREGULATED NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS. IN CONTRAST TO THE UNALTERABLE NATURE OF GENETIC PATTERNS, EPIGENETIC CHANGES CAN BE REVERSED, OPENING UP NEW POSSIBILITIES IN DEVELOPING THERAPIES FOR VARIOUS METABOLIC DISORDERS AND DISEASES. THIS REVIEW DISCUSSES THE CURRENT STATE OF THE NRF2-MEDIATED ANTIOXIDATIVE AND CHEMOPREVENTIVE ACTIVITIES OF SEVERAL NATURAL PHYTOCHEMICALS, INCLUDING SULFORAPHANE, RESVERATROL, CURCUMIN, LUTEOLIN, COROSOLIC ACID, APIGENIN, AND MOST OTHER COMPOUNDS THAT HAVE BEEN FOUND TO ACTIVATE NRF2. THIS EPIGENETIC REVERSAL OF HYPERMETHYLATED NRF2 STATES PROVIDES NEW OPPORTUNITIES FOR RESEARCH INTO DIETARY PHYTOCHEMISTRY THAT AFFECTS THE HUMAN EPIGENOME AND THE POSSIBILITY FOR CUTTING-EDGE APPROACHES TO TARGET NRF2-MEDIATED SIGNALING TO PREVENT CHRONIC DISORDERS. 2023 5 6045 30 THE COMPLEXITY OF THE NRF2 PATHWAY: BEYOND THE ANTIOXIDANT RESPONSE. THE NF-E2-RELATED FACTOR 2 (NRF2)-MEDIATED SIGNALLING PATHWAY PROVIDES LIVING ORGANISMS AN EFFICIENT AND PIVOTAL LINE OF DEFENSIVE TO COUNTERACT ENVIRONMENTAL INSULTS AND ENDOGENOUS STRESSORS. NRF2 COORDINATES THE BASAL AND INDUCIBLE EXPRESSION OF ANTIOXIDANT AND PHASE II DETOXIFICATION ENZYMES TO ADAPT TO DIFFERENT STRESS CONDITIONS. THE STABILITY AND CELLULAR DISTRIBUTION OF NRF2 IS TIGHTLY CONTROLLED BY ITS INHIBITORY BINDING PROTEIN KELCH-LIKE ECH-ASSOCIATED PROTEIN 1. NRF2 SIGNALLING IS ALSO REGULATED BY POSTTRANSLATIONAL, TRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS, AS WELL AS BY OTHER PROTEIN PARTNERS, INCLUDING P62, P21 AND IQ MOTIF-CONTAINING GTPASE ACTIVATING PROTEIN 1. MANY STUDIES HAVE DEMONSTRATED THAT NRF2 IS A PROMISING TARGET FOR PREVENTING CARCINOGENESIS AND OTHER CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND PULMONARY INJURY. HOWEVER, CONSTITUTIVE ACTIVATION OF NRF2 IN ADVANCED CANCER CELLS MAY CONFER DRUG RESISTANCE. HERE, WE REVIEW THE MOLECULAR MECHANISMS OF NRF2 SIGNALLING, THE DIVERSE CLASSES OF NRF2 ACTIVATORS, INCLUDING BIOACTIVE NUTRIENTS AND OTHER CHEMICALS, AND THE CELLULAR FUNCTIONS AND DISEASE RELEVANCE OF NRF2 AND DISCUSS THE DUAL ROLE OF NRF2 IN DIFFERENT CONTEXTS. 2015 6 1413 38 DIETARY PHYTOCHEMICALS AND CANCER CHEMOPREVENTION: A PERSPECTIVE ON OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETICS. OXIDATIVE STRESS OCCURS WHEN CELLULAR REACTIVE OXYGEN SPECIES LEVELS EXCEED THE SELF-ANTIOXIDANT CAPACITY OF THE BODY. OXIDATIVE STRESS INDUCES MANY PATHOLOGICAL CHANGES, INCLUDING INFLAMMATION AND CANCER. CHRONIC INFLAMMATION IS BELIEVED TO BE STRONGLY ASSOCIATED WITH THE MAJOR STAGES OF CARCINOGENESIS. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) PATHWAY PLAYS A CRUCIAL ROLE IN REGULATING OXIDATIVE STRESS AND INFLAMMATION BY MANIPULATING KEY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES VIA THE ANTIOXIDANT RESPONSE ELEMENT. MANY DIETARY PHYTOCHEMICALS WITH CANCER CHEMOPREVENTIVE PROPERTIES, SUCH AS POLYPHENOLS, ISOTHIOCYANATES, AND TRITERPENOIDS, EXERT ANTIOXIDANT AND ANTI-INFLAMMATORY FUNCTIONS BY ACTIVATING THE NRF2 PATHWAY. FURTHERMORE, EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND MIRNA-MEDIATED POST-TRANSCRIPTIONAL ALTERATIONS, ALSO LEAD TO VARIOUS CARCINOGENESIS PROCESSES BY SUPPRESSING CANCER REPRESSOR GENE TRANSCRIPTION. USING EPIGENETIC RESEARCH TOOLS, INCLUDING NEXT-GENERATION SEQUENCING TECHNOLOGIES, MANY DIETARY PHYTOCHEMICALS ARE SHOWN TO MODIFY AND REVERSE ABERRANT EPIGENETIC/EPIGENOME CHANGES, POTENTIALLY LEADING TO CANCER PREVENTION/TREATMENT. THUS, THE BENEFICIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON CANCER DEVELOPMENT WARRANT FURTHER INVESTIGATION TO PROVIDE ADDITIONAL IMPETUS FOR CLINICAL TRANSLATIONAL STUDIES. 2016 7 3527 41 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 8 4836 34 ONCOGENIC FUNCTIONS OF THE TRANSCRIPTION FACTOR NRF2. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR THAT CONTROLS THE EXPRESSION OF A LARGE POOL OF ANTIOXIDANT AND CYTOPROTECTIVE GENES REGULATING THE CELLULAR RESPONSE TO OXIDATIVE AND ELECTROPHILIC STRESS. NRF2 IS NEGATIVELY REGULATED BY KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1) AND, UPON STIMULATION BY AN OXIDATIVE OR ELECTROPHILIC INSULT, IS RAPIDLY ACTIVATED BY PROTEIN STABILIZATION. OWING TO ITS CYTOPROTECTIVE FUNCTIONS, NRF2 HAS BEEN TRADITIONALLY STUDIED IN THE FIELD OF CHEMOPREVENTION; HOWEVER, THERE IS ACCUMULATED EVIDENCE THAT KEAP1/NRF2 MUTATIONS OR UNBALANCED REGULATION THAT LEADS TO OVEREXPRESSION OR HYPERACTIVATION OF NRF2 MAY PARTICIPATE IN TUMORIGENESIS AND BE INVOLVED IN CHEMORESISTANCE OF A WIDE NUMBER OF SOLID CANCERS AND LEUKEMIAS. IN ADDITION TO PROTECTING CELLS FROM REACTIVE OXYGEN SPECIES, NRF2 SEEMS TO PLAY A DIRECT ROLE IN CELL GROWTH CONTROL AND IS RELATED TO APOPTOSIS-REGULATING PATHWAYS. MOREOVER, NRF2 ACTIVITY IS CONNECTED WITH ONCOGENIC KINASE PATHWAYS, STRUCTURAL PROTEINS, HORMONAL REGULATION, OTHER TRANSCRIPTION FACTORS, AND EPIGENETIC ENZYMES INVOLVED IN THE PATHOGENESIS OF VARIOUS TYPES OF TUMORS. THE AIM OF THIS REVIEW IS TO COMPILE AND SUMMARIZE EXISTING KNOWLEDGE OF THE ONCOGENIC FUNCTIONS OF NRF2 TO PROVIDE A SOLID BASIS FOR ITS POTENTIAL USE AS A MOLECULAR MARKER AND PHARMACOLOGICAL TARGET IN CANCER. 2013 9 3207 31 HDACI: CELLULAR EFFECTS, OPPORTUNITIES FOR RESTORATIVE DENTISTRY. ACETYLATION OF HISTONE AND NON-HISTONE PROTEINS ALTERS GENE EXPRESSION AND INDUCES A HOST OF CELLULAR EFFECTS. THE ACETYLATION PROCESS IS HOMEOSTATICALLY BALANCED BY TWO GROUPS OF CELLULAR ENZYMES, HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). HAT ACTIVITY RELAXES THE STRUCTURE OF THE HUMAN CHROMATIN, RENDERING IT TRANSCRIPTIONALLY ACTIVE, THEREBY INCREASING GENE EXPRESSION. IN CONTRAST, HDAC ACTIVITY LEADS TO GENE SILENCING. THE ENZYMATIC BALANCE CAN BE 'TIPPED' BY HISTONE DEACETYLASE INHIBITORS (HDACI), LEADING TO AN ACCUMULATION OF ACETYLATED PROTEINS, WHICH SUBSEQUENTLY MODIFY CELLULAR PROCESSES INCLUDING STEM CELL DIFFERENTIATION, CELL CYCLE, APOPTOSIS, GENE EXPRESSION, AND ANGIOGENESIS. THERE IS A VARIETY OF NATURAL AND SYNTHETIC HDACI AVAILABLE, AND THEIR PLEIOTROPIC EFFECTS HAVE CONTRIBUTED TO DIVERSE CLINICAL APPLICATIONS, NOT ONLY IN CANCER BUT ALSO IN NON-CANCER AREAS, SUCH AS CHRONIC INFLAMMATORY DISEASE, BONE ENGINEERING, AND NEURODEGENERATIVE DISEASE. INDEED, IT APPEARS THAT HDACI-MODULATED EFFECTS MAY DIFFER BETWEEN 'NORMAL' AND TRANSFORMED CELLS, PARTICULARLY WITH REGARD TO REACTIVE OXYGEN SPECIES ACCUMULATION, APOPTOSIS, PROLIFERATION, AND CELL CYCLE ARREST. THE POTENTIAL BENEFICIAL EFFECTS OF HDACI FOR HEALTH, RESULTING FROM THEIR ABILITY TO REGULATE GLOBAL GENE EXPRESSION BY EPIGENETIC MODIFICATION OF DNA-ASSOCIATED PROTEINS, ALSO OFFER POTENTIAL FOR APPLICATION WITHIN RESTORATIVE DENTISTRY, WHERE THEY MAY PROMOTE DENTAL TISSUE REGENERATION FOLLOWING PULPAL DAMAGE. 2011 10 2002 25 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 11 5972 27 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 12 1902 32 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 13 834 36 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 14 2339 52 EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING. THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) SIGNALING AXIS SERVES AS A "MASTER REGULATOR" IN RESPONSE TO OXIDATIVE/ELECTROPHILIC STRESSES AND CHEMICAL INSULTS THROUGH THE COORDINATED INDUCTION OF A WIDE ARRAY OF CYTOPROTECTIVE GENES. THEREFORE, ACTIVATION OF NRF2 IS CONSIDERED TO BE AN IMPORTANT APPROACH FOR PREVENTING CHRONIC DISEASES TRIGGERED BY STRESSES AND TOXINS, INCLUDING CANCER. DESPITE EXTENSIVE STUDIES SUGGESTED THAT THE KEAP1-NRF2 SIGNALING PATHWAY IS SUBJECT TO MULTIPLE LAYERS OF REGULATION AT THE TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL LEVELS, THE POTENTIAL EPIGENETIC REGULATION OF NRF2 AND KEAP1 HAS BEGUN TO BE RECOGNIZED ONLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS, HERITABLE ALTERATIONS IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN THE PRIMARY DNA SEQUENCE, HAVE BEEN REPORTED TO BE PROFOUNDLY INVOLVED IN OXIDATIVE STRESS RESPONSES. IN THIS REVIEW, WE DISCUSS THE LATEST FINDINGS REGARDING THE EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING BY DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS. THE CROSSTALK AMONG THESE EPIGENETIC MODIFICATIONS IN THE REGULATION OF KEAP1-NRF2 SIGNALING PATHWAYS IS ALSO DISCUSSED. STUDIES OF THE EPIGENETIC MODIFICATION OF NRF2 AND KEAP1 HAVE NOT ONLY ENHANCED OUR UNDERSTANDING OF THIS COMPLEX CELLULAR DEFENSE SYSTEM BUT HAVE ALSO PROVIDED POTENTIAL NEW THERAPEUTIC TARGETS FOR THE PREVENTION OF CERTAIN DISEASES. 2015 15 2055 34 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 16 2308 31 EPIGENETIC REGULATION OF CHEMOKINE (CC-MOTIF) LIGAND 2 IN INFLAMMATORY DISEASES. APPROPRIATE RESPONSES TO INFLAMMATION ARE CONDUCIVE TO PATHOGEN ELIMINATION AND TISSUE REPAIR, WHILE UNCONTROLLED INFLAMMATORY REACTIONS ARE LIKELY TO RESULT IN THE DAMAGE OF TISSUES. CHEMOKINE (CC-MOTIF) LIGAND 2 (CCL2) IS THE MAIN CHEMOKINE AND ACTIVATOR OF MONOCYTES, MACROPHAGES, AND NEUTROPHILS. CCL2 PLAYED A KEY ROLE IN AMPLIFYING AND ACCELERATING THE INFLAMMATORY CASCADE AND IS CLOSELY RELATED TO CHRONIC NON-CONTROLLABLE INFLAMMATION (CIRRHOSIS, NEUROPATHIC PAIN, INSULIN RESISTANCE, ATHEROSCLEROSIS, DEFORMING ARTHRITIS, ISCHEMIC INJURY, CANCER, ETC.). THE CRUCIAL REGULATORY ROLES OF CCL2 MAY PROVIDE POTENTIAL TARGETS FOR THE TREATMENT OF INFLAMMATORY DISEASES. THEREFORE, WE PRESENTED A REVIEW OF THE REGULATORY MECHANISMS OF CCL2. GENE EXPRESSION IS LARGELY AFFECTED BY THE STATE OF CHROMATIN. DIFFERENT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, POST-TRANSLATIONAL MODIFICATION OF HISTONES, HISTONE VARIANTS, ATP-DEPENDENT CHROMATIN REMODELLING, AND NON-CODING RNA, COULD AFFECT THE 'OPEN' OR 'CLOSED' STATE OF DNA, AND THEN SIGNIFICANTLY AFFECT THE EXPRESSION OF TARGET GENES. SINCE MOST EPIGENETIC MODIFICATIONS ARE PROVEN TO BE REVERSIBLE, TARGETING THE EPIGENETIC MECHANISMS OF CCL2 IS EXPECTED TO BE A PROMISING THERAPEUTIC STRATEGY FOR INFLAMMATORY DISEASES. THIS REVIEW FOCUSES ON THE EPIGENETIC REGULATION OF CCL2 IN INFLAMMATORY DISEASES. 2023 17 5937 35 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 18 1251 29 CURRENT PERSPECTIVES ON ROLE OF CHROMATIN MODIFICATIONS AND DEACETYLASES IN LUNG INFLAMMATION IN COPD. CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION ARE CRITICAL FOR SUSTAINED AND ABNORMAL INFLAMMATORY RESPONSE SEEN IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BECAUSE THE ACTIVITIES OF ENZYMES THAT REGULATE THESE EPIGENETIC MODIFICATIONS ARE ALTERED IN RESPONSE TO CIGARETTE SMOKE. CIGARETTE SMOKE INDUCES CHROMATIN MODIFICATIONS AND EPIGENETIC CHANGES BY CAUSING POST-TRANSLATIONAL MODIFICATIONS OF HISTONE ACETYLTRANSFERASES, AND HISTONE/NON-HISTONE DEACETYLASES (HDACS), SUCH AS HDAC2 AND SIRTUIN 1 (SIRT1), WHICH LEADS TO CHROMATIN REMODELING. IN THIS REVIEW, WE DISCUSSED THE CURRENT KNOWLEDGE ON CIGARETTE SMOKE/OXIDANTS-INDUCED POST-TRANSLATIONAL MODIFICATIONS OF DEACETYLASES (HDAC2 AND SIRT1), DISRUPTION OF HDAC2/SIRT1-RELA/P65 COREPRESSOR COMPLEX ASSOCIATED WITH ACETYLATION OF RELA/P65, AND CHROMATIN MODIFICATIONS (HISTONE H3 PHOSPHO-ACETYLATION) LEADING TO SUSTAINED PRO-INFLAMMATORY GENE TRANSCRIPTION. KNOWLEDGE ON MOLECULAR MECHANISMS OF EPIGENETIC CHANGES IN ABNORMAL LUNG INFLAMMATION WILL HELP IN UNDERSTANDING THE PATHOPHYSIOLOGY OF COPD WHICH MAY LEAD TO THE DEVELOPMENT OF NOVEL EPIGENETIC THERAPIES IN THE NEAR FUTURE. 2009 19 4772 33 NUCLEAR SIRTUINS AND INFLAMMATORY SIGNALING PATHWAYS. THE REGULATION OF CHRONIC INFLAMMATION HAS RECEIVED CONSIDERABLE RESEARCH ATTENTION IN RECENT YEARS BECAUSE OF ITS CONTRIBUTION TO THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS ARTHRITIS, DIABETES, METABOLIC SYNDROME AND OBESITY. THUS, STRATEGIES THAT INHIBIT THE INFLAMMATORY STATE MAY BE BENEFICIAL IN IMPROVING THE PATHOPHYSIOLOGY OF SEVERAL INFLAMMATION-RELATED DISORDERS. SIRTUINS ARE A FAMILY OF HISTONE DEACETYLASES THAT CONTAIN SEVEN ENZYMATIC ACTIVITIES IN MAMMALS (SIRT1-SIRT7) AND FUNCTION TO SUPPRESS GENE TRANSCRIPTION BY EPIGENETIC MECHANISMS. NUCLEAR SIRTUINS (SIRT 1, 2, 6 AND 7) IN PARTICULAR MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF INFLAMMATORY RESPONSES. IN THE PRESENT REVIEW, WE ASSESSED THE ROLES OF NUCLEAR SIRTUINS IN INFLAMMATORY REACTIONS: SIRT1 HAS BEEN SHOWN TO SUPPRESS NF-KAPPAB ACTIVITY, THE MASTER REGULATOR OF CELLULAR INFLAMMATORY RESPONSE, DECREASE COX-2 AND INOS PRODUCTION, AND INCREASE ANTIOXIDANT GENE EXPRESSION THAT SUPPRESSED INFLAMMATION. SIRT2 ACTIVITY INCLUDED THE DEACETYLATION OF P65 SUBUNIT OF NF-KAPPABETA AND RIP-1, WHILE SIRT6 HAS BEEN SHOWN TO INTERACT WITH P65/RELA BOUND TO THE NF-KAPPABETA PROMOTER REGION AND REPRESS TRANSCRIPTIONAL ACTIVITY. FURTHERMORE, RECENT STUDIES HAVE SHOWN THAT THE ABSENCE OF SIRT7 PRODUCED AN INCREASE IN INFLAMMATION, ILLUSTRATING THAT SIRT7 ALSO FUNCTIONED TO DECREASE INFLAMMATION. GIVEN THEIR SIGNIFICANT ROLES IN THE REGULATION OF CHRONIC INFLAMMATION, NUCLEAR SIRTUINS REPRESENT POTENTIAL THERAPEUTIC TARGETS IN THE CONTROL OF CHRONIC INFLAMMATORY DISEASES. 2017 20 5562 28 ROLE OF HISTONE DEACETYLASES IN PANCREAS: IMPLICATIONS FOR PATHOGENESIS AND THERAPY. IN THE LAST YEARS, OUR KNOWLEDGE OF THE PATHOGENESIS IN ACUTE AND CHRONIC PANCREATITIS (AP/CP) AS WELL AS IN PANCREATIC CANCEROGENESIS HAS SIGNIFICANTLY DIVERSIFIED. NEVERTHELESS, THE MEDICINAL THERAPEUTIC OPTIONS ARE STILL LIMITED AND THERAPEUTIC SUCCESS AND PATIENT OUTCOME ARE POOR. EPIGENETIC DEREGULATION OF GENE EXPRESSION IS KNOWN TO CONTRIBUTE TO DEVELOPMENT AND PROGRESSION OF AP AND CP AS WELL AS OF PANCREATIC CANCER. THEREFORE, THE SELECTIVE INHIBITION OF ABERRANTLY ACTIVE EPIGENETIC REGULATORS CAN BE AN EFFECTIVE OPTION FOR FUTURE THERAPIES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT REMOVE AN ACETYL GROUP FROM HISTONE TAILS, THEREBY CAUSING CHROMATIN COMPACTION AND REPRESSION OF TRANSCRIPTION. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE CURRENTLY AVAILABLE LITERATURE ADDRESSING THE ROLE OF HDACS IN THE PANCREAS AND IN PANCREATIC DISEASES. IN PANCREATIC CANCEROGENESIS, HDACS PLAY A ROLE IN THE IMPORTANT PROCESS OF EPITHELIAL-MESENCHYMAL-TRANSITION, UBIQUITIN-PROTEASOME PATHWAY AND, HYPOXIA-INDUCIBLE-FACTOR-1-ANGIOGENESIS. FINALLY, WE FOCUS ON HDACS AS POTENTIAL THERAPEUTIC TARGETS BY SUMMARIZING CURRENTLY AVAILABLE HISTONE DEACETYLASE INHIBITORS. 2015