1 2889 132 GAIN-OF-FUNCTION STAT1 MUTATIONS IMPAIR STAT3 ACTIVITY IN PATIENTS WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) TRIGGERED PRODUCTION OF TH-17 CYTOKINES MEDIATES PROTECTIVE IMMUNITY AGAINST FUNGI. MUTATIONS AFFECTING THE STAT3/INTERLEUKIN 17 (IL-17) PATHWAY CAUSE SELECTIVE SUSCEPTIBILITY TO FUNGAL (CANDIDA) INFECTIONS, A HALLMARK OF CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC). IN PATIENTS WITH AUTOSOMAL DOMINANT CMC, WE AND OTHERS PREVIOUSLY REPORTED DEFECTIVE TH17 RESPONSES AND UNDERLYING GAIN-OF-FUNCTION (GOF) STAT1 MUTATIONS, BUT HOW THIS AFFECTS STAT3 FUNCTION LEADING TO DECREASED IL-17 IS UNCLEAR. WE ALSO ASSESSED HOW GOF-STAT1 MUTATIONS AFFECT STAT3 ACTIVATION, DNA BINDING, GENE EXPRESSION, CYTOKINE PRODUCTION, AND EPIGENETIC MODIFICATIONS. WE EXCLUDED IMPAIRED STAT3 PHOSPHORYLATION, NUCLEAR TRANSLOCATION, AND SEQUESTRATION OF STAT3 INTO STAT1/STAT3 HETERODIMERS AND CONFIRM SIGNIFICANTLY REDUCED TRANSCRIPTION OF STAT3-INDUCIBLE GENES (RORC/IL-17/IL-22/IL-10/C-FOS/SOCS3/C-MYC) AS LIKELY UNDERLYING MECHANISM. STAT BINDING TO THE HIGH AFFINITY SIS-INDUCIBLE ELEMENT WAS INTACT BUT BINDING TO AN ENDOGENOUS STAT3 DNA TARGET WAS IMPAIRED. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION WAS REVERSED BY INHIBITING STAT1 ACTIVATION WITH FLUDARABINE OR ENHANCING HISTONE, BUT NOT STAT1 OR STAT3 ACETYLATION WITH HISTONE DEACETYLASE (HDAC) INHIBITORS TRICHOSTATIN A OR ITF2357. SILENCING HDAC1, HDAC2, AND HDAC3 INDICATED A ROLE FOR HDAC1 AND 2. REDUCED STAT3-DEPENDENT GENE TRANSCRIPTION UNDERLIES LOW TH-17 RESPONSES IN GOF-STAT1 CMC, WHICH CAN BE REVERSED BY INHIBITING ACETYLATION, OFFERING NOVEL TARGETS FOR FUTURE THERAPIES. 2015 2 3781 43 INTERFERON SIGNATURE IN PATIENTS WITH STAT1 GAIN-OF-FUNCTION MUTATION IS EPIGENETICALLY DETERMINED. STAT1 GAIN-OF-FUNCTION (GOF) VARIANTS LEAD TO DEFECTIVE TH17 CELL DEVELOPMENT AND CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC), BUT FREQUENTLY ALSO TO AUTOIMMUNITY. STIMULATION OF CELLS WITH STAT1 INDUCING CYTOKINES LIKE INTERFERONS (IFN) RESULT IN HYPERPHOSPHORYLATION AND DELAYED DEPHOSPHORYLATION OF GOF STAT1. HOWEVER, THE MECHANISM HOW THE DELAYED DEPHOSPHORYLATION EXACTLY CAUSES THE INCREASED EXPRESSION OF STAT1-DEPENDENT GENES, AND HOW THE INTRACELLULAR SIGNAL TRANSDUCTION FROM CYTOKINE RECEPTORS IS AFFECTED, REMAINS UNKNOWN. IN THIS STUDY WE SHOW THAT THE CIRCULATING LEVELS OF IFN-ALPHA WERE NOT PERSISTENTLY ELEVATED IN STAT1 GOF PATIENTS. NEVERTHELESS, THE EXPRESSION OF INTERFERON SIGNATURE GENES WAS EVIDENT EVEN IN THE PATIENT WITH LOW OR UNDETECTABLE SERUM IFN-ALPHA LEVELS. CHROMATIN IMMUNOPRECIPITATION (CHIP) EXPERIMENTS REVEALED THAT THE ACTIVE CHROMATIN MARK TRIMETHYLATION OF LYSINE 4 OF HISTONE 3 (H3K4ME3), WAS SIGNIFICANTLY ENRICHED IN AREAS ASSOCIATED WITH INTERFERON-STIMULATED GENES IN STAT1 GOF CELLS IN COMPARISON TO CELLS FROM HEALTHY DONORS. THIS SUGGESTS THAT THE CHROMATIN BINDING OF GOF STAT1 VARIANT PROMOTES EPIGENETIC CHANGES COMPATIBLE WITH HIGHER GENE EXPRESSION AND ELEVATED REACTIVITY TO TYPE I INTERFERONS, AND POSSIBLY PREDISPOSES FOR INTERFERON-RELATED AUTOIMMUNITY. THE RESULTS ALSO SUGGEST THAT EPIGENETIC REWIRING MAY BE RESPONSIBLE FOR TREATMENT FAILURE OF JANUS KINASE 1/2 (JAK1/2) INHIBITORS IN CERTAIN PATIENTS. 2019 3 1303 40 DEFECTIVE TRAINED IMMUNITY IN PATIENTS WITH STAT-1-DEPENDENT CHRONIC MUCOCUTANEAOUS CANDIDIASIS. PATIENTS WITH SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1)-DEPENDENT CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC) AND PATIENTS WITH STAT3-DEPENDENT HYPER-IMMUNOGLOBULIN (IG)E SYNDROME (HIES) DISPLAY DEFECTS IN T HELPER TYPE 17 (TH17) CYTOKINE PRODUCTION CAPACITY. DESPITE THIS SIMILAR IMMUNE DEFECT IN TH17 FUNCTION, THEY SHOW IMPORTANT DIFFERENCES IN THE TYPE OF INFECTIONS TO WHICH THEY ARE SUSCEPTIBLE. RECENTLY, OUR GROUP REPORTED DIFFERENTIAL REGULATION OF STAT-1 AND STAT-3 TRANSCRIPTION FACTORS DURING EPIGENETIC REPROGRAMMING OF TRAINED IMMUNITY, AN IMPORTANT HOST DEFENCE MECHANISM BASED ON INNATE IMMUNE MEMORY. WE THEREFORE HYPOTHESIZED THAT STAT1 AND STAT3 DEFECTS HAVE DIFFERENT EFFECTS ON TRAINED IMMUNITY, AND THIS MAY PARTLY EXPLAIN THE DIFFERENCES BETWEEN CMC AND HIES REGARDING THE SUSCEPTIBILITY TO INFECTIONS. INDEED, WHILE TRAINED IMMUNITY WAS NORMALLY INDUCED IN CELLS ISOLATED FROM PATIENTS WITH HIES, THE INDUCTION OF INNATE TRAINING WAS DEFECTIVE IN CMC PATIENTS. THIS DEFECT WAS SPECIFIC FOR TRAINING WITH CANDIDA ALBICANS, THE MAIN PATHOGEN ENCOUNTERED IN CMC, AND IT INVOLVED A TYPE II INTERFERON-DEPENDENT MECHANISM. THESE FINDINGS DESCRIBE THE ROLE OF STAT-1 FOR THE INDUCTION OF TRAINED IMMUNITY, AND MAY CONTRIBUTE TO THE UNDERSTANDING OF THE DIFFERENCES IN SUSCEPTIBILITY TO INFECTION BETWEEN CMC AND HIES PATIENTS. THIS STUDY COULD ALSO PROVIDE DIRECTIONS FOR PERSONALIZED IMMUNOTHERAPY IN PATIENTS SUFFERING FROM THESE IMMUNODEFICIENCIES. 2015 4 3527 32 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 5 5795 36 STAT3 INDUCTION OF MIR-146B FORMS A FEEDBACK LOOP TO INHIBIT THE NF-KAPPAB TO IL-6 SIGNALING AXIS AND STAT3-DRIVEN CANCER PHENOTYPES. INTERLEUKIN-6 (IL-6)-MEDIATED ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) IS A MECHANISM BY WHICH CHRONIC INFLAMMATION CAN CONTRIBUTE TO CANCER AND IS A COMMON ONCOGENIC EVENT. WE DISCOVERED A PATHWAY, THE LOSS OF WHICH IS ASSOCIATED WITH PERSISTENT STAT3 ACTIVATION IN HUMAN CANCER. WE FOUND THAT THE GENE ENCODING THE TUMOR SUPPRESSOR MICRORNA MIR-146B IS A DIRECT STAT3 TARGET GENE, AND ITS EXPRESSION WAS INCREASED IN NORMAL BREAST EPITHELIAL CELLS BUT DECREASED IN TUMOR CELLS. METHYLATION OF THE MIR-146B PROMOTER, WHICH INHIBITED STAT3-MEDIATED INDUCTION OF EXPRESSION, WAS INCREASED IN PRIMARY BREAST CANCERS. MOREOVER, WE FOUND THAT MIR-146B INHIBITED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT PRODUCTION OF IL-6, SUBSEQUENT STAT3 ACTIVATION, AND IL-6/STAT3-DRIVEN MIGRATION AND INVASION IN BREAST CANCER CELLS, THEREBY ESTABLISHING A NEGATIVE FEEDBACK LOOP. IN ADDITION, HIGHER EXPRESSION OF MIR-146B WAS POSITIVELY CORRELATED WITH PATIENT SURVIVAL IN BREAST CANCER SUBTYPES WITH INCREASED IL6 EXPRESSION AND STAT3 PHOSPHORYLATION. OUR RESULTS IDENTIFY AN EPIGENETIC MECHANISM OF CROSSTALK BETWEEN STAT3 AND NF-KAPPAB RELEVANT TO CONSTITUTIVE STAT3 ACTIVATION IN MALIGNANCY AND THE ROLE OF INFLAMMATION IN ONCOGENESIS. 2014 6 1479 27 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 7 5088 37 PIPERLONGUMINE REGULATES EPIGENETIC MODULATION AND ALLEVIATES PSORIASIS-LIKE SKIN INFLAMMATION VIA INHIBITION OF HYPERPROLIFERATION AND INFLAMMATION. PSORIASIS IS AN AUTOIMMUNE SKIN DISEASE, WHERE CHRONIC IMMUNE RESPONSES DUE TO EXAGGERATED CYTOKINE SIGNALING, ABNORMAL DIFFERENTIATION, AND EVASION OF KERATINOCYTES APOPTOSIS PLAYS A CRUCIAL ROLE IN MEDIATING ABNORMAL KERATINOCYTES HYPERPROLIFERATION. FROM THE THERAPEUTIC PERSPECTIVE, THE MOLECULES WITH STRONG ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY PROPERTIES COULD HAVE TREMENDOUS RELEVANCE. IN THIS STUDY, WE DEMONSTRATED THAT PIPERLONGUMINE (PPL) TREATMENT EFFECTIVELY ABROGATED THE HYPERPROLIFERATION AND DIFFERENTIATION OF KERATINOCYTES BY INDUCING ROS-MEDIATED LATE APOPTOSIS WITH LOSS OF MITOCHONDRIAL MEMBRANE POTENTIAL. BESIDES, THE ARREST OF CELL CYCLE WAS FOUND AT SUB-G1 PHASE AS A RESULT OF DNA FRAGMENTATION. MOLECULARLY, INHIBITION OF STAT3 AND AKT SIGNALING WAS OBSERVED WITH A DECREASE IN PROLIFERATIVE MARKERS SUCH AS PCNA, KI67, AND CYCLIN D1 ALONG WITH ANTI-APOPTOTIC BCL-2 PROTEIN EXPRESSION. KERATIN 17 IS A CRITICAL REGULATOR OF KERATINOCYTE DIFFERENTIATION, AND IT WAS FOUND TO BE DOWNREGULATED WITH PPL SIGNIFICANTLY. FURTHERMORE, PROMINENT ANTI-INFLAMMATORY EFFECTS WERE OBSERVED BY INHIBITION OF LIPOPOLYSACCHARIDE (LPS)/IMIQUIMOD (IMQ)-INDUCED P65 NF-KAPPAB SIGNALING CASCADE AND STRONGLY INHIBITED THE PRODUCTION OF CYTOKINE STORM INVOLVED IN PSORIASIS-LIKE SKIN INFLAMMATION, THUS LED TO THE RESTORATION OF NORMAL EPIDERMAL ARCHITECTURE WITH REDUCTION OF EPIDERMAL HYPERPLASIA AND SPLENOMEGALY. IN ADDITION, PPL EPIGENETICALLY INHIBITED HISTONE-MODIFYING ENZYMES, WHICH INCLUDE HISTONE DEACETYLASES (HDACS) OF CLASS I (HDAC1-4) AND CLASS II (HDAC6) EVALUATED BY IMMUNOBLOTTING AND HDAC ENZYME ASSAY KIT. IN ADDITION, OUR RESULTS SHOW THAT PPL EFFECTIVELY INHIBITS THE NUCLEAR TRANSLOCATION OF P65 AND A HISTONE MODULATOR HDAC3, THUS SEQUESTERED IN THE CYTOPLASM OF MACROPHAGES. FURTHERMORE, PPL EFFECTIVELY ENHANCED THE PROTEIN-PROTEIN INTERACTIONS OF HDAC3 AND P65 WITH IKAPPABALPHA, WHICH WAS DISRUPTED BY LPS STIMULATION AND WERE EVALUATED BY CO-IP AND MOLECULAR MODELING. COLLECTIVELY, OUR FINDINGS INDICATE THAT PIPERLONGUMINE MAY SERVE AS AN ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY AGENT AND COULD SERVE AS A POTENTIAL THERAPEUTIC OPTION IN TREATING PSORIASIS. 2020 8 6765 36 ZINC DEFICIENCY LEADS TO REDUCED INTERLEUKIN-2 PRODUCTION BY ACTIVE GENE SILENCING DUE TO ENHANCED CREMALPHA EXPRESSION IN T CELLS. BACKGROUND & AIMS: THE MICRONUTRIENT ZINC IS ESSENTIAL FOR PROPER IMMUNE FUNCTION. CONSEQUENTLY, ZINC DEFICIENCY LEADS TO IMPAIRED IMMUNE FUNCTION, AS SEEN IN DECREASED SECRETION OF INTERLEUKIN (IL)-2 BY T CELLS. ALTHOUGH THIS ASSOCIATION HAS BEEN KNOWN SINCE THE LATE 1980S, THE UNDERLYING MOLECULAR MECHANISMS ARE STILL UNKNOWN. ZINC DEFICIENCY AND REDUCED IL-2 LEVELS ARE ESPECIALLY FOUND IN THE ELDERLY, WHICH IN TURN ARE PRONE TO CHRONIC DISEASES. HERE, WE DESCRIBE A NEW MOLECULAR LINK BETWEEN ZINC DEFICIENCY AND REDUCED IL-2 EXPRESSION IN T CELLS. METHODS: THE EFFECTS OF ZINC DEFICIENCY WERE FIRST INVESTIGATED IN VITRO IN THE HUMAN T CELL LINES JURKAT AND HUT-78 AND COMPLEMENTED BY IN VIVO DATA FROM ZINC-SUPPLEMENTED PIGS. A SHORT- AND LONG-TERM MODEL FOR ZINC DEFICIENCY WAS ESTABLISHED. ZINC LEVELS WERE DETECTED BY FLOW CYTOMETRY AND EXPRESSION PROFILES WERE INVESTIGATED ON THE MRNA AND PROTEIN LEVEL. RESULTS: THE EXPRESSION OF THE TRANSCRIPTION FACTOR CAMP-RESPONSIVE-ELEMENT MODULATOR ALPHA (CREMALPHA) IS INCREASED DURING ZINC DEFICIENCY IN VITRO, DUE TO INCREASED PROTEIN PHOSPHATASE 2A (PP2A) ACTIVITY, RESULTING IN DECREASED IL-2 PRODUCTION. ADDITIONALLY, ZINC SUPPLEMENTATION IN VIVO REDUCED CREMALPHA LEVELS CAUSING INCREASED IL-2 EXPRESSION. ON EPIGENETIC LEVELS INCREASED CREMALPHA BINDING TO THE IL-2 PROMOTER IS MEDIATED BY HISTONE DEACETYLASE 1 (HDAC1). THE HDAC1 ACTIVITY IS INHIBITED BY ZINC. MOREOVER, DEACETYLATION OF THE ACTIVATING HISTONE MARK H3K9 WAS INCREASED UNDER ZINC DEFICIENCY, RESULTING IN REDUCED IL-2 EXPRESSION. CONCLUSIONS: WITH THE TRANSCRIPTION FACTOR CREMALPHA A MOLECULAR LINK WAS UNCOVERED, CONNECTING ZINC DEFICIENCY WITH REDUCED IL-2 PRODUCTION DUE TO ENHANCED PP2A AND HDAC1 ACTIVITY. 2021 9 3893 22 LACTATE INDUCES METABOLIC AND EPIGENETIC REPROGRAMMING OF PRO-INFLAMMATORY TH17 CELLS. INCREASED LACTATE LEVELS IN THE TISSUE MICROENVIRONMENT ARE A WELL-KNOWN FEATURE OF CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF LACTATE IN REGULATING T CELL FUNCTION REMAINS CONTROVERSIAL. HERE, WE DEMONSTRATE THAT EXTRACELLULAR LACTATE PREDOMINANTLY INDUCES DEREGULATION OF THE TH17-SPECIFIC GENE EXPRESSION PROGRAM BY MODULATING THE METABOLIC AND EPIGENETIC STATUS OF TH17 CELLS. FOLLOWING LACTATE TREATMENT, TH17 CELLS SIGNIFICANTLY REDUCED THEIR IL-17A PRODUCTION AND UPREGULATED FOXP3 EXPRESSION THROUGH ROS-DRIVEN IL-2 SECRETION. MOREOVER, WE OBSERVED INCREASED LEVELS OF GENOME-WIDE HISTONE H3K18 LACTYLATION, A RECENTLY DESCRIBED MARKER FOR ACTIVE CHROMATIN IN MACROPHAGES, IN LACTATE-TREATED TH17 CELLS. IN ADDITION, WE SHOW THAT HIGH LACTATE CONCENTRATIONS SUPPRESS TH17 PATHOGENICITY DURING INTESTINAL INFLAMMATION IN MICE. THESE RESULTS INDICATE THAT LACTATE IS CAPABLE OF REPROGRAMMING PRO-INFLAMMATORY T CELL PHENOTYPES INTO REGULATORY T CELLS. 2022 10 5972 28 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 11 4284 31 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 12 3204 42 HDAC3 REGULATES GINGIVAL FIBROBLAST INFLAMMATORY RESPONSES IN PERIODONTITIS. HISTONE DEACETYLASES (HDACS) ARE IMPORTANT REGULATORS OF GENE EXPRESSION THAT ARE ABERRANTLY REGULATED IN SEVERAL INFLAMMATORY AND INFECTIOUS DISEASES. HDAC INHIBITORS (HDACI) SUPPRESS INFLAMMATORY ACTIVATION OF VARIOUS CELL TYPES THROUGH EPIGENETIC AND NON-EPIGENETIC MECHANISMS, AND AMELIORATE PATHOLOGY IN A MOUSE MODEL OF PERIODONTITIS. ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) SIGNIFICANTLY CONTRIBUTES TO THE DEVELOPMENT OF PERIODONTITIS AND THE ANAEROBIC BACTERIUM PORPHYROMONAS GINGIVALIS PLAYS A KEY ROLE IN DRIVING CHRONIC INFLAMMATION. HERE, WE ANALYZED THE ROLE OF HDACS IN INFLAMMATORY RESPONSES OF GFS. PAN-HDACI SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) AND/OR ITF2357 (GIVINOSTAT) SIGNIFICANTLY REDUCED TNFALPHA- AND P. GINGIVALIS-INDUCIBLE EXPRESSION AND/OR PRODUCTION OF A CLUSTER OF INFLAMMATORY MEDIATORS IN HEALTHY DONOR GFS (IL1B, CCL2, CCL5, CXCL10, COX2, AND MMP3) WITHOUT AFFECTING CELL VIABILITY. SELECTIVE INHIBITION OF HDAC3/6, BUT NOT SPECIFIC HDAC1, HDAC6, OR HDAC8 INHIBITION, REPRODUCED THE SUPPRESSIVE EFFECTS OF PAN-HDACI ON THE INFLAMMATORY GENE EXPRESSION PROFILE INDUCED BY TNFALPHA AND P. GINGIVALIS, SUGGESTING A CRITICAL ROLE FOR HDAC3 IN GF INFLAMMATORY ACTIVATION. CONSISTENTLY, SILENCING OF HDAC3 EXPRESSION WITH SIRNA LARGELY RECAPITULATED THE EFFECTS OF HDAC3/6I ON MRNA LEVELS OF INFLAMMATORY MEDIATORS IN P. GINGIVALIS-INFECTED GFS. IN CONTRAST, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS REMAINED UNAFFECTED BY HDACI. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES AND NFKAPPAB SIGNALING WAS UNAFFECTED BY GLOBAL OR HDAC3/6-SELECTIVE HDACI, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR GENE SUPPRESSION BY HDACI. FINALLY, PAN-HDACI AND HDAC3/6I SUPPRESSED P. GINGIVALIS-INDUCED EXPRESSION OF IL1B, CCL2, CCL5, CXCL10, MMP1, AND MMP3 IN GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS IDENTIFY HDAC3 AS AN IMPORTANT REGULATOR OF INFLAMMATORY GENE EXPRESSION IN GFS AND SUGGEST THAT THERAPEUTIC TARGETING OF HDAC ACTIVITY, IN PARTICULAR HDAC3, MAY BE CLINICALLY BENEFICIAL IN SUPPRESSING INFLAMMATION IN PERIODONTAL DISEASE. 2020 13 2068 29 EPIGENETIC CONTROL OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 BY HDAC-MEDIATED RECRUITMENT OF P300. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ARE THE MOST WIDELY USED MEDICINE TO TREAT PAIN AND INFLAMMATION, AND TO INHIBIT PLATELET FUNCTION. UNDERSTANDING THE EXPRESSION REGULATION OF ENZYMES OF THE PROSTANOID PATHWAY IS OF GREAT MEDICAL RELEVANCE. HISTONE ACETYLATION CRUCIALLY CONTROLS GENE EXPRESSION. WE SET OUT TO IDENTIFY THE IMPACT OF HISTONE DEACETYLASES (HDACS) ON THE GENERATION OF PROSTANOIDS AND EXAMINE THE CONSEQUENCES ON VASCULAR FUNCTION. HDAC INHIBITION (HDACI) WITH THE PAN-HDAC INHIBITOR, VORINOSTAT, ATTENUATED PROSTAGLANDIN (PG)E(2) GENERATION IN THE MURINE VASCULATURE AND IN HUMAN VASCULAR SMOOTH MUSCLE CELLS. IN LINE WITH THIS, THE EXPRESSION OF THE KEY ENZYME FOR PGE(2) SYNTHESIS, MICROSOMAL PGE SYNTHASE-1 (PTGES1), WAS REDUCED BY HDACI. ACCORDINGLY, THE RELAXATION TO ARACHIDONIC ACID WAS DECREASED AFTER EX VIVO INCUBATION OF MURINE VESSELS WITH HDACI. TO IDENTIFY THE UNDERLYING MECHANISM, CHROMATIN IMMUNOPRECIPITATION (CHIP) AND CHIP-SEQUENCING ANALYSIS WERE PERFORMED. THESE RESULTS SUGGEST THAT HDACS ARE INVOLVED IN THE RECRUITMENT OF THE TRANSCRIPTIONAL ACTIVATOR P300 TO THE PTGES1 GENE AND THAT HDACI PREVENTED THIS EFFECT. IN LINE WITH THE ACETYLTRANSFERASE ACTIVITY OF P300, H3K27 ACETYLATION WAS REDUCED AFTER HDACI AND RESULTED IN THE FORMATION OF HETEROCHROMATIN IN THE PTGES1 GENE. IN CONCLUSION, HDAC ACTIVITY MAINTAINS PTGES1 EXPRESSION BY RECRUITING P300 TO ITS GENE. 2017 14 3415 34 HSP90 INHIBITION INCREASES SOCS3 TRANSCRIPT AND REGULATES MIGRATION AND CELL DEATH IN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC OR TRANSCRIPTIONAL SILENCING OF IMPORTANT TUMOR SUPPRESSORS HAS BEEN DESCRIBED TO CONTRIBUTE TO CELL SURVIVAL AND TUMORIGENESIS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). USING GENE EXPRESSION MICROARRAY ANALYSIS, WE FOUND THAT THOUSANDS OF GENES ARE REPRESSED MORE THAN 2-FOLD IN CLL COMPARED TO NORMAL B CELLS; HOWEVER THERAPEUTIC APPROACHES TO REVERSE THIS HAVE BEEN LIMITED IN CLL. FOLLOWING TREATMENT WITH THE HSP90 INHIBITOR 17-DMAG, A SIGNIFICANT NUMBER OF THESE REPRESSED GENES WERE SIGNIFICANTLY RE-EXPRESSED. ONE OF THE GENES SIGNIFICANTLY REPRESSED IN CLL AND UP-REGULATED BY 17-DMAG WAS SUPPRESSOR OF CYTOKINE SIGNALING 3, (SOCS3). SOCS3 HAS BEEN SHOWN TO BE SILENCED IN SOLID TUMORS AS WELL AS MYELOID LEUKEMIA; HOWEVER LITTLE IS KNOWN ABOUT THE REGULATION IN CLL. WE FOUND THAT 17-DMAG INDUCES EXPRESSION OF SOCS3 BY VIA THE ACTIVATION OF P38 SIGNALING, AND SUBSEQUENTLY INHIBITS AKT AND STAT3 PHOSPHORYLATION RESULTING IN DOWNSTREAM EFFECTS ON CELL MIGRATION AND SURVIVAL. WE THEREFORE SUGGEST THAT SOCS3 IS AN IMPORTANT SIGNALING PROTEIN IN CLL, AND HSP90 INHIBITORS REPRESENT A NOVEL APPROACH TO TARGET TRANSCRIPTIONAL REPRESSION IN B CELL LYMPHOPROLIFERATIVE DISORDERS WHICH EXHIBIT A SUBSTANTIAL DEGREE OF GENE REPRESSION. 2016 15 3339 41 HISTONE DEACETYLASE ISOFORMS DIFFERENTIALLY MODULATE INFLAMMATORY AND AUTOANTIBODY RESPONSES IN A MOUSE MODEL OF MYASTHENIA GRAVIS. MYASTHENIA GRAVIS (MG) IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC MUSCLE FATIGUE AND WEAKNESS CAUSED BY AUTOANTIBODIES AND COMPLEMENT-MEDIATED DAMAGE AT NEUROMUSCULAR JUNCTIONS. HISTONE DEACETYLASES (HDACS) ARE CRUCIAL EPIGENETIC REGULATORS OF PROINFLAMMATORY GENE EXPRESSION; HOWEVER, IT IS UNCLEAR WHETHER HDACS MODULATE CHRONIC INFLAMMATION OR AUTOANTIBODY PRODUCTION ASSOCIATED WITH MG PATHOGENESIS. WE EXAMINED EXPRESSION PROFILES AND SERUM LEVELS OF KEY INFLAMMATORY CYTOKINES (IL-6 AND IL-21) AND ACETYLCHOLINE RECEPTOR (ACHR)-SPECIFIC AUTOANTIBODIES FOLLOWING PHARMACOLOGICAL INHIBITION OF KEY HDAC ISOFORMS IN A MOUSE MODEL OF MG. WE FOUND THAT HDAC INHIBITION SIGNIFICANTLY REDUCED THE PRODUCTION OF IL-6, BUT NOT IL-21, IN ACHR-STIMULATED PBMCS AND SPLENOCYTES (N = 5 PER GROUP). TRICHOSTATIN (PAN-HDAC INHIBITOR) TREATMENT OF MG-PBMCS (N = 2) ALSO EXHIBITED REDUCED PRODUCTION OF INDUCED IL-6. ALTHOUGH HDAC1 INHIBITION LOWERED IL-6 LEVELS THE MOST, HDAC2 INHIBITION DEPLETED INTRACELLULAR IL-6 AND MARKEDLY REDUCED SERUM ANTI-ACHR IGG2B IN EAMG MICE. THE TRANSCRIPTOMIC PROFILING AND PATHWAY MAPPING ALSO REVEALED THAT AUTOIMMUNITY-LINKED, MAJOR CELL SIGNALING PATHWAYS WERE DIFFERENTIALLY ALTERED BY HDAC1/2 INHIBITION. HDAC INHIBITION-MEDIATED REDUCTION IN IL-6 AND AUTOANTIBODY LEVELS ALSO CORRELATED WITH MILDER DISEASE AND PRESERVATION OF MUSCLE ACHR IN THE TREATED MICE. OVERALL, OUR FINDINGS REVEALED ISOFORM-SPECIFIC FUNCTIONAL VARIANCE OF HDACS IN REDUCING INFLAMMATION AND IDENTIFIED HDAC-REGULATED MANY GENES UNDERLYING SPECIFIC INFLAMMATORY AND AUTOANTIBODY PATHWAYS IN EAMG. THUS, THE STUDY PROVIDES A RATIONALE FOR FURTHER RESEARCH TO EVALUATE THE HDACS OR THEIR GENE TARGETS AS A POTENTIAL ADJUNCT TREATMENT FOR MG. 2021 16 5975 28 TET1 IS AN IMPORTANT TRANSCRIPTIONAL ACTIVATOR OF TNFALPHA EXPRESSION IN MACROPHAGES. ACTIVATION OF MACROPHAGES AND OVEREXPRESSION OF TNFALPHA IS ASSOCIATED WITH THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. HOWEVER, THE MECHANISMS LEADING TO TNFALPHA OVEREXPRESSION ARE STILL UNKNOWN. 5-METHYLOCYTOSINE (5-MC) IS AN EPIGENETIC MODIFICATION THAT IS ASSOCIATED WITH SILENCED GENES. RECENT STUDIES SHOWED THAT IT IS CONVERTED TO 5-HYDROXYLMETHYLOCYTOSINE (5-HMC) AND REACTIVATES GENE EXPRESSION THROUGH THE ACTION OF THE FAMILY OF TEN-ELEVEN-TRANSLOCATION (TET1-3) ENZYMES. IN THIS STUDY, WE SHOW THAT 5-HMC LEVELS ARE INCREASED GLOBALLY AND SPECIFICALLY IN THE TNFALPHA PROMOTER DURING THE DIFFERENTIATION OF MONOCYTES TO MACROPHAGES. IN ADDITION, THE LEVELS OF 5-HMC ARE INCREASED UPON LPS STIMULATION OF MACROPHAGES. FURTHERMORE, CRIPSR STABLE KNOCKOUT OF TET1 DECREASES THE EXPRESSION OF TNFALPHA AND OTHER PRO-INFLAMMATORY CYTOKINES. IN CONCLUSION, WE SHOWED THAT TET1 CONTRIBUTES TO THE ACTIVATION OF MACROPHAGES POSSIBLY THROUGH REGULATION OF 5-HYDROXYMETHYLATION IN THE PROMOTER OF PRO-INFLAMMATORY CYTOKINE GENES. THE TET1 ENZYME COULD BE A PROMISING THERAPEUTIC TARGET TO INHIBIT THE PERSISTENT INFLAMMATION CAUSED BY MACROPHAGES IN CHRONIC INFLAMMATORY DISEASES. 2019 17 5872 29 SUSTAINED TNF-ALPHA STIMULATION LEADS TO TRANSCRIPTIONAL MEMORY THAT GREATLY ENHANCES SIGNAL SENSITIVITY AND ROBUSTNESS. TRANSCRIPTIONAL MEMORY ALLOWS CERTAIN GENES TO RESPOND TO PREVIOUSLY EXPERIENCED SIGNALS MORE ROBUSTLY. HOWEVER, WHETHER AND HOW THE KEY PROINFLAMMATORY CYTOKINE TNF-ALPHA MEDIATES TRANSCRIPTIONAL MEMORY ARE POORLY UNDERSTOOD. USING HEK293F CELLS AS A MODEL SYSTEM, WE REPORT THAT SUSTAINED TNF-ALPHA STIMULATION INDUCES TRANSCRIPTIONAL MEMORY DEPENDENT ON TET ENZYMES. THE HYPOMETHYLATED STATUS OF TRANSCRIPTIONAL REGULATORY REGIONS CAN BE INHERITED, FACILITATING NF-KAPPAB BINDING AND MORE ROBUST SUBSEQUENT ACTIVATION. A HIGH INITIAL METHYLATION LEVEL AND CPG DENSITY AROUND KAPPAB SITES ARE CORRELATED WITH THE FUNCTIONAL POTENTIAL OF TRANSCRIPTIONAL MEMORY MODULES. INTERESTINGLY, THE CALCB GENE, ENCODING THE PROVEN MIGRAINE THERAPEUTIC TARGET CGRP, EXHIBITS THE BEST TRANSCRIPTIONAL MEMORY. A NEIGHBORING PRIMATE-SPECIFIC ENDOGENOUS RETROVIRUS STIMULATES MORE RAPID, MORE STRONG, AND AT LEAST 100-FOLD MORE SENSITIVE CALCB INDUCTION IN SUBSEQUENT TNF-ALPHA STIMULATION. OUR STUDY REVEALS THAT TNF-ALPHA-MEDIATED TRANSCRIPTIONAL MEMORY IS GOVERNED BY ACTIVE DNA DEMETHYLATION AND GREATLY SENSITIZES MEMORY GENES TO MUCH LOWER DOSES OF INFLAMMATORY CUES. 2020 18 3323 34 HISTONE DEACETYLASE 1 (HDAC1): A KEY PLAYER OF T CELL-MEDIATED ARTHRITIS. RHEUMATOID ARTHRITIS (RA) REPRESENTS A CHRONIC T CELL-MEDIATED INFLAMMATORY AUTOIMMUNE DISEASE. STUDIES HAVE SHOWN THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF RA. HISTONE DEACETYLASES (HDACS) REPRESENT ONE IMPORTANT GROUP OF EPIGENETIC REGULATORS. HOWEVER, THE ROLE OF INDIVIDUAL HDAC MEMBERS FOR THE PATHOGENESIS OF ARTHRITIS IS STILL UNKNOWN. IN THIS STUDY WE DEMONSTRATE THAT MICE WITH A T CELL-SPECIFIC DELETION OF HDAC1 (HDAC1-CKO) ARE RESISTANT TO THE DEVELOPMENT OF COLLAGEN-INDUCED ARTHRITIS (CIA), WHEREAS THE ANTIBODY RESPONSE TO COLLAGEN TYPE II WAS UNDISTURBED, INDICATING AN UNALTERED T CELL-MEDIATED B CELL ACTIVATION. THE INFLAMMATORY CYTOKINES IL-17 AND IL-6 WERE SIGNIFICANTLY DECREASED IN SERA OF HDAC1-CKO MICE. IL-6 TREATED HDAC1-DEFICIENT CD4(+) T CELLS SHOWED AN IMPAIRED UPREGULATION OF CCR6. SELECTIVE INHIBITION OF CLASS I HDACS WITH THE HDAC INHIBITOR MS-275 UNDER TH17-SKEWING CONDITIONS INHIBITED THE UPREGULATION OF CHEMOKINE RECEPTOR 6 (CCR6) IN MOUSE AND HUMAN CD4(+) T CELLS. ACCORDINGLY, ANALYSIS OF HUMAN RNA-SEQUENCING (RNA-SEQ) DATA AND HISTOLOGICAL ANALYSIS OF SYNOVIAL TISSUE SAMPLES FROM HUMAN RA PATIENTS REVEALED THE EXISTENCE OF CD4(+)CCR6(+) CELLS WITH ENHANCED HDAC1 EXPRESSION. OUR DATA INDICATE A KEY ROLE FOR HDAC1 FOR THE PATHOGENESIS OF CIA AND SUGGEST THAT HDAC1 AND OTHER CLASS I HDACS MIGHT BE PROMISING TARGETS OF SELECTIVE HDAC INHIBITORS (HDACI) FOR THE TREATMENT OF RA. 2020 19 2247 21 EPIGENETIC MODULATION OF MACROPHAGE POLARIZATION PREVENTS LUMBAR DISC DEGENERATION. INFLAMMATION PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT OF LUMBAR DISC DEGENERATION (LDD), ALTHOUGH THE EXACT EFFECTS OF MACROPHAGE SUBTYPES ON LDD REMAIN UNCLEAR. BASED ON PREVIOUS STUDIES, WE HYPOTHESIZED THAT M2-POLARIZATION OF LOCAL MACROPHAGES AND SIMULTANEOUS SUPPRESSION OF THEIR PRODUCTION OF FIBROTIC TRANSFORMING GROWTH FACTOR BETA 1 (TGFBETA1) COULD INHIBIT PROGRESSION OF LDD. THUS, WE APPLIED AN ORTHOTOPIC INJECTION OF ADENO-ASSOCIATED VIRUS (AAV) CARRYING SHRNA FOR DNA METHYLTRANSFERASE 1 (DNMT1) AND/OR SHRNA FOR TGFBETA1 UNDER A MACROPHAGE-SPECIFIC CD68 PROMOTER TO SPECIFICALLY TARGET LOCAL MACROPHAGES IN A MOUSE MODEL FOR LDD. WE FOUND THAT SHDNMT1 SIGNIFICANTLY REDUCED LEVELS OF THE PRO-INFLAMMATORY CYTOKINES TNFALPHA, IL-1BETA AND IL-6, SIGNIFICANTLY INCREASED LEVELS OF THE ANTI-INFLAMMATORY CYTOKINES IL-4 AND IL-10, SIGNIFICANTLY INCREASED M2 MACROPHAGE POLARIZATION, SIGNIFICANTLY REDUCED CELL APOPTOSIS IN THE DISC DEGENERATION ZONE AND SIGNIFICANTLY REDUCED LDD-ASSOCIATED PAIN. THE ANTI-APOPTOTIC AND ANTI-PAIN EFFECTS WERE FURTHER STRENGTHENED BY CO-APPLICATION OF SHTGFBETA1. TOGETHER, THESE DATA SUGGEST THAT M2 POLARIZATION OF MACROPHAGES INDUCED BY BOTH EPIGENETIC MODULATION AND SUPPRESSED PRODUCTION AND RELEASE OF TGFBETA1 FROM POLARIZED M2 MACROPHAGES, MAY HAVE A DEMONSTRABLE THERAPEUTIC EFFECT ON LDD. 2020 20 1036 29 CLASS I HISTONE DEACETYLASES REGULATE P53/NF-KAPPAB CROSSTALK IN CANCER CELLS. THE TRANSCRIPTION FACTORS NF-KAPPAB AND P53 AS WELL AS THEIR CROSSTALK DETERMINE THE FATE OF TUMOR CELLS UPON THERAPEUTIC INTERVENTIONS. REPLICATIVE STRESS AND CYTOKINES PROMOTE SIGNALING CASCADES THAT LEAD TO THE CO-REGULATION OF P53 AND NF-KAPPAB. CONSEQUENTLY, NUCLEAR P53/NF-KAPPAB SIGNALING COMPLEXES ACTIVATE NF-KAPPAB-DEPENDENT SURVIVAL GENES. THE 18 HISTONE DEACETYLASES (HDACS) ARE EPIGENETIC MODULATORS THAT FALL INTO FOUR CLASSES (I-IV). INHIBITORS OF HISTONE DEACETYLASES (HDACI) BECOME INCREASINGLY APPRECIATED AS ANTI-CANCER AGENTS. BASED ON THEIR EFFECTS ON P53 AND NF-KAPPAB, WE ADDRESSED WHETHER CLINICALLY RELEVANT HDACI AFFECT THE NF-KAPPAB/P53 CROSSTALK. THE CHEMOTHERAPEUTICS HYDROXYUREA, ETOPOSIDE, AND FLUDARABINE HALT CELL CYCLE PROGRESSION, INDUCE DNA DAMAGE, AND LEAD TO DNA FRAGMENTATION. THESE AGENTS CO-INDUCE P53 AND NF-KAPPAB-DEPENDENT GENE EXPRESSION IN CELL LINES FROM BREAST AND COLON CANCER AND IN PRIMARY CHRONIC LYMPHATIC LEUKEMIA (CLL) CELLS. USING SPECIFIC HDACI, WE FIND THAT THE CLASS I SUBGROUP OF HDACS, BUT NOT THE CLASS IIB DEACETYLASE HDAC6, ARE REQUIRED FOR THE HYDROXYUREA-INDUCED CROSSTALK BETWEEN P53 AND NF-KAPPAB. HDACI DECREASE THE BASAL AND STRESS-INDUCED EXPRESSION OF P53 AND BLOCK NF-KAPPAB-REGULATED GENE EXPRESSION. WE FURTHER SHOW THAT CLASS I HDACI INDUCE SENESCENCE IN PANCREATIC CANCER CELLS WITH MUTANT P53. 2017