1 5795 104 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 2 2889 36 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 3 4284 50 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 4 1479 25 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 5 3781 27 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 6 5429 14 REGULATION OF TYPE I INTERFERON RESPONSES. TYPE I INTERFERONS (IFNS) ACTIVATE INTRACELLULAR ANTIMICROBIAL PROGRAMMES AND INFLUENCE THE DEVELOPMENT OF INNATE AND ADAPTIVE IMMUNE RESPONSES. CANONICAL TYPE I IFN SIGNALLING ACTIVATES THE JANUS KINASE (JAK)-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) PATHWAY, LEADING TO TRANSCRIPTION OF IFN-STIMULATED GENES (ISGS). HOST, PATHOGEN AND ENVIRONMENTAL FACTORS REGULATE THE RESPONSES OF CELLS TO THIS SIGNALLING PATHWAY AND THUS CALIBRATE HOST DEFENCES WHILE LIMITING TISSUE DAMAGE AND PREVENTING AUTOIMMUNITY. HERE, WE SUMMARIZE THE SIGNALLING AND EPIGENETIC MECHANISMS THAT REGULATE TYPE I IFN-INDUCED STAT ACTIVATION AND ISG TRANSCRIPTION AND TRANSLATION. THESE REGULATORY MECHANISMS DETERMINE THE BIOLOGICAL OUTCOMES OF TYPE I IFN RESPONSES AND WHETHER PATHOGENS ARE CLEARED EFFECTIVELY OR CHRONIC INFECTION OR AUTOIMMUNE DISEASE ENSUES. 2014 7 598 25 BETA-ADRENERGIC SIGNALING PROMOTES TUMOR ANGIOGENESIS AND PROSTATE CANCER PROGRESSION THROUGH HDAC2-MEDIATED SUPPRESSION OF THROMBOSPONDIN-1. CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING HAVE BEEN SHOWN TO PROMOTE CANCER PROGRESSION, WHOSE UNDERLYING MECHANISMS ARE LARGELY UNCLEAR, ESPECIALLY THE INVOLVEMENT OF EPIGENETIC REGULATION. HISTONE DEACETYLASE-2 (HDAC2), AN EPIGENETIC REGULATOR, IS CRITICAL FOR STRESS-INDUCED CARDIAC HYPERTROPHY. IT IS UNKNOWN WHETHER IT IS NECESSARY FOR BETA-ADRENERGIC SIGNALING-PROMOTED CANCER PROGRESSION. USING XENOGRAFT MODELS, WE SHOWED THAT CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING PROMOTE ANGIOGENESIS AND PROSTATE CANCER PROGRESSION. HDAC2 WAS INDUCED BY BETA-ADRENERGIC SIGNALING IN VITRO AND IN MOUSE XENOGRAFTS. WE NEXT UNCOVERED THAT HDAC2 IS A DIRECT TARGET OF CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) THAT IS ACTIVATED BY BETA-ADRENERGIC SIGNALING. NOTABLY, HDAC2 IS NECESSARY FOR BETA-ADRENERGIC SIGNALING TO INDUCE ANGIOGENESIS. WE FURTHER DEMONSTRATED THAT, UPON CREB ACTIVATION, HDAC2 REPRESSES THROMBOSPONDIN-1 (TSP1), A POTENT ANGIOGENESIS INHIBITOR, THROUGH EPIGENETIC REGULATION. TOGETHER, THESE DATA ESTABLISH A NOVEL PATHWAY THAT HDAC2 AND TSP1 ACT DOWNSTREAM OF CREB ACTIVATION IN BETA-ADRENERGIC SIGNALING TO PROMOTE CANCER PROGRESSION. 2017 8 5732 31 SMAD4 TGF-BETA-INDEPENDENT FUNCTION PRECONDITIONS NAIVE CD8+ T CELLS TO PREVENT SEVERE CHRONIC INTESTINAL INFLAMMATION. SMAD4, A MEDIATOR OF TGF-BETA SIGNALING, PLAYS AN IMPORTANT ROLE IN T CELLS TO PREVENT INFLAMMATORY BOWEL DISEASE (IBD). HOWEVER, THE PRECISE MECHANISMS UNDERLYING THIS CONTROL REMAIN ELUSIVE. USING BOTH GENETIC AND EPIGENETIC APPROACHES, WE REVEALED AN UNEXPECTED MECHANISM BY WHICH SMAD4 PREVENTS NAIVE CD8+ T CELLS FROM BECOMING PATHOGENIC FOR THE GUT. PRIOR TO THE ENGAGEMENT OF THE TGF-BETA RECEPTOR, SMAD4 RESTRAINS THE EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LANDSCAPE OF THE TGF-BETA SIGNATURE IN NAIVE CD8+ T CELLS. MECHANISTICALLY, PRIOR TO TGF-BETA SIGNALING, SMAD4 BINDS TO PROMOTERS AND ENHANCERS OF SEVERAL TGF-BETA TARGET GENES, AND BY REGULATING HISTONE DEACETYLATION, SUPPRESSES THEIR EXPRESSION. CONSEQUENTLY, REGARDLESS OF A TGF-BETA SIGNAL, SMAD4 LIMITS THE EXPRESSION OF TGF-BETA NEGATIVE FEEDBACK LOOP GENES, SUCH AS SMAD7 AND SKI, AND LIKELY CONDITIONS CD8+ T CELLS FOR THE IMMUNOREGULATORY EFFECTS OF TGF-BETA. IN ADDITION, SMAD4 ABLATION CONFERRED NAIVE CD8+ T CELLS WITH BOTH A SUPERIOR SURVIVAL CAPACITY, BY ENHANCING THEIR RESPONSE TO IL-7, AS WELL AS AN ENHANCED CAPACITY TO BE RETAINED WITHIN THE INTESTINAL EPITHELIUM, BY PROMOTING THE EXPRESSION OF ITGAE, WHICH ENCODES THE INTEGRIN CD103. ACCUMULATION, EPITHELIAL RETENTION, AND ESCAPE FROM TGF-BETA CONTROL ELICITED CHRONIC MICROBIOTA-DRIVEN CD8+ T CELL ACTIVATION IN THE GUT. HENCE, IN A TGF-BETA-INDEPENDENT MANNER, SMAD4 IMPRINTS A PROGRAM THAT PRECONDITIONS NAIVE CD8+ T CELL FATE, PREVENTING IBD. 2022 9 730 31 CANCER CELLS RESISTANT TO IMMUNE CHECKPOINT BLOCKADE ACQUIRE INTERFERON-ASSOCIATED EPIGENETIC MEMORY TO SUSTAIN T CELL DYSFUNCTION. PROLONGED INTERFERON (IFN) SIGNALING IN CANCER CELLS CAN PROMOTE RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOW CANCER CELLS RETAIN EFFECTS OF PROLONGED IFN STIMULATION TO COORDINATE RESISTANCE IS UNCLEAR. WE SHOW THAT, ACROSS HUMAN AND/OR MOUSE TUMORS, IMMUNE DYSFUNCTION IS ASSOCIATED WITH CANCER CELLS ACQUIRING EPIGENETIC FEATURES OF INFLAMMATORY MEMORY. HERE, INFLAMMATORY MEMORY DOMAINS, MANY OF WHICH ARE INITIATED BY CHRONIC IFN-GAMMA, ARE MAINTAINED BY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)1 AND IFN REGULATORY FACTOR (IRF)3 AND LINK HISTONE 3 LYSINE 4 MONOMETHYLATION (H3K4ME1)-MARKED CHROMATIN ACCESSIBILITY TO INCREASED EXPRESSION OF A SUBSET OF IFN-STIMULATED GENES (ISGS). THESE ISGS INCLUDE THE RNA SENSOR OAS1 THAT AMPLIFIES TYPE I IFN (IFN-I) AND IMMUNE INHIBITORY GENES. ABROGATING CANCER CELL IFN-I SIGNALING RESTORES ANTI-PROGRAMMED CELL DEATH PROTEIN 1 (PD1) RESPONSE BY INCREASING IFN-GAMMA IN IMMUNE CELLS, PROMOTING DENDRITIC CELL AND CD8(+) T CELL INTERACTIONS, AND EXPANDING T CELLS TOWARD EFFECTOR-LIKE STATES RATHER THAN EXHAUSTED STATES. THUS, CANCER CELLS ACQUIRE INFLAMMATORY MEMORY TO AUGMENT A SUBSET OF ISGS THAT PROMOTE AND PREDICT IFN-DRIVEN IMMUNE DYSFUNCTION. 2023 10 3289 37 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 11 2380 31 EPIGENETIC REGULATION OF WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. CERTAIN WNT AND WNT NETWORK TARGET GENES ARE EXPRESSED AT HIGHER OR LOWER LEVELS IN CHRONIC LYMPHOCYTIC LEUKEMIA COMPARED WITH NORMAL B-CELLS. THIS INCLUDES UPREGULATION OF NUCLEAR COMPLEX GENES, AS WELL AS GENES FOR CYTOPLASMIC PROTEINS AND WNT LIGANDS AND THEIR COGNATE RECEPTORS. IN ADDITION, EPIGENETIC SILENCING OF SEVERAL NEGATIVE REGULATORS OF THE WNT PATHWAY HAVE BEEN IDENTIFIED. THE BALANCE BETWEEN EPIGENETIC DOWNREGULATION OF NEGATIVE EFFECTOR GENES AND INCREASED EXPRESSION OF POSITIVE EFFECTOR GENES DEMONSTRATE THAT THE EPIGENETIC DOWNREGULATION OF WNT ANTAGONISTS IS ONE MECHANISM, PERHAPS THE MAIN MECHANISM, THAT IS PERMISSIVE TO ACTIVE WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MOREOVER, CONSTITUTIVE ACTIVATION OF THE WNT NETWORK AND TARGET GENES IS LIKELY TO IMPACT ON ADDITIONAL INTERACTING SIGNALING PATHWAYS. BASED ON PUBLISHED STUDIES, WE PROPOSE A MODEL OF WNT SIGNALING THAT INVOLVES MAINLY PERMISSIVE EXPRESSION, AND SOMETIMES OVEREXPRESSION, OF POSITIVE EFFECTORS AND DOWNREGULATION OF NEGATIVE REGULATORS IN THE NETWORK. IN THIS MODEL, DNA METHYLATION, HISTONE MODIFICATIONS AND ALTERED EXPRESSION OF MICRORNA MOLECULES INTERACT TO ALLOW CONTINUOUS WNT SIGNALING. 2010 12 4357 34 MIR-30E* IS OVEREXPRESSED IN PROSTATE CANCER AND PROMOTES NF-KAPPAB-MEDIATED PROLIFERATION AND TUMOR GROWTH. ACCORDING TO THE CDC PROSTATE CANCER (CAP) HAS THE HIGHEST INCIDENCE AND SECOND HIGHEST MORTALITY RATE AMONGST CANCERS IN AMERICAN MEN. CONSTITUTIVE NF-KAPPAB ACTIVATION IS A HALLMARK OF CAP AND THIS PATHWAY DRIVES MANY PRO-TUMORIGENIC CHARACTERISTICS OF CAP CELLS, INCLUDING CELL PROLIFERATION AND SURVIVAL. AN ACTIVATED NF-KAPPAB GENE SIGNATURE IS PREDICTIVE OF CAP PROGRESSION AND BIOCHEMICAL RECURRENCE FOLLOWING THERAPEUTIC INTERVENTION. HOWEVER, THE MECHANISMS THAT PERPETUATE NF-KAPPAB ACTIVATION ARE INCOMPLETELY UNDERSTOOD. GENES THAT CONTROL NF-KAPPAB ACTIVITY ARE RARELY MUTATED IN CAP SUGGESTING THAT EPIGENETIC MECHANISMS MAY CONTRIBUTE TO CONSTITUTIVE NF-KAPPAB ACTIVATION. MICRORNAS (MIRS) EPIGENETICALLY REGULATE MANY GENES INVOLVED WITH NF-KAPPAB ACTIVATION. IKAPPABALPHA IS A DIRECT INHIBITOR OF NF-KAPPAB; IT BINDS TO AND SEQUESTERS NF-KAPPAB IN THE CYTOPLASM RESULTING IN FUNCTIONAL INHIBITION. IKAPPABALPHA IS A TARGET GENE OF MIR-30E* YET THE EXPRESSION AND ONCOLOGICAL IMPACT OF MIR-30E* IN CAP IS UNKNOWN. WE REPORT THAT MIR-30E* EXPRESSION IS ELEVATED IN MULTIPLE MURINE MODELS OF CAP AND IS MOST PRONOUNCED IN LATE STAGE DISEASE. MIR-30E* DRIVES CAP PROLIFERATION AND TUMOR GROWTH THROUGH INHIBITION OF IKAPPABALPHA, WHICH RESULTS IN CHRONIC ACTIVATION OF NF-KAPPAB. ADDITIONALLY, WE SHOW THAT INHIBITION OF MIR-30E* IMPROVES CHEMOTHERAPEUTIC CONTROL OF CAP. THUS, MIR-30E* MAY PROVE TO BE A NOVEL CLINICAL TARGET WHOSE INHIBITION LEADS TO DECREASED CAP CELL PROLIFERATION AND SENSITIZATION OF CAP CELLS TO CHEMOTHERAPEUTICS. 2017 13 1905 36 ENHANCER OF ZESTE HOMOLOG 2 CONTRIBUTES TO APOPTOSIS BY INACTIVATING JANUS KINASE 2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN INFLAMMATORY BOWEL DISEASE. BACKGROUND: INFLAMMATORY BOWEL DISEASE (IBD) IS A PREVALENT WORLDWIDE HEALTH PROBLEM FEATURED BY RELAPSING, CHRONIC GASTROINTESTINAL INFLAMMATION. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A CRITICAL EPIGENETIC REGULATOR IN DIFFERENT PATHOLOGICAL MODELS, SUCH AS CANCER AND INFLAMMATION. HOWEVER, THE ROLE OF EZH2 IN THE IBD DEVELOPMENT IS STILL OBSCURE. AIM: TO EXPLORE THE EFFECT OF EZH2 ON IBD PROGRESSION AND THE UNDERLYING MECHANISM. METHODS: THE IBD MOUSE MODEL WAS CONDUCTED BY ADDING DEXTRAN SODIUM SULFATE (DSS), AND THE EFFECT OF EZH2 ON DSS-INDUCED COLITIS WAS ASSESSED IN THE MODEL. THE FUNCTION OF EZH2 IN REGULATING APOPTOSIS AND PERMEABILITY WAS EVALUATED BY ANNEXIN V-FITC APOPTOSIS DETECTION KIT, TRANSEPITHELIAL ELECTRICAL RESISTANCE ANALYSIS, AND WESTERN BLOT ANALYSIS OF RELATED MARKERS, INCLUDING ZONA OCCLUDENS 1, CLAUDIN-5, AND OCCLUDIN, IN NCM460 AND FETAL HUMAN COLON (FHC) CELLS. THE MECHANICAL INVESTIGATION WAS PERFORMED BY QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION, WESTERN BLOT ANALYSIS, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: THE COLON LENGTH WAS INHIBITED IN THE DSS-TREATED MICE AND WAS ENHANCED BY THE EZH2 DEPLETION IN THE SYSTEM. DSS TREATMENT CAUSED A DECREASED HISTOLOGICAL SCORE IN THE MICE, WHICH WAS REVERSED BY EZH2 DEPLETION. THE INFLAMMATORY CYTOKINES, SUCH AS TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-6, AND INTERLEUKIN-1BETA, WERE INDUCED IN THE DSS-TREATED MICE, IN WHICH THE DEPLETION OF EZH2 COULD REVERSE THIS EFFECT. MOREOVER, THE TUMOR NECROSIS FACTOR-ALPHA TREATMENT INDUCED THE APOPTOSIS OF NCM460 AND FHC CELLS, IN WHICH EZH2 DEPLETION COULD REVERSE THIS EFFECT IN THE CELLS. MOREOVER, THE DEPLETION OF EZH2 ATTENUATED PERMEABILITY OF COLONIC EPITHELIAL CELLS. MECHANICALLY, THE DEPLETION OF EZH2 OR EZH2 INHIBITOR GSK343 WAS ABLE TO ENHANCE THE EXPRESSION AND THE PHOSPHORYLATION OF JANUS KINASE 2 (JK2) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION IN THE NCM460 AND FHC CELLS. SPECIFICALLY, EZH2 INACTIVATED JAK2 EXPRESSION BY REGULATING HISTONE H3K27ME3. JAK2 INHIBITOR TG101348 WAS ABLE TO REVERSE EZH2 KNOCKDOWN-MEDIATED COLONIC EPITHELIAL CELL PERMEABILITY AND APOPTOSIS. CONCLUSION: THUS, WE CONCLUDED THAT EZH2 CONTRIBUTED TO APOPTOSIS AND INFLAMMATORY RESPONSE BY INACTIVATING JAK2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN IBD. EZH2 MAY BE APPLIED AS A POTENTIAL TARGET FOR IBD THERAPY. 2021 14 5223 31 PRIMARY MURINE CD4+ T CELLS FAIL TO ACQUIRE THE ABILITY TO PRODUCE EFFECTOR CYTOKINES WHEN ACTIVE RAS IS PRESENT DURING TH1/TH2 DIFFERENTIATION. CONSTITUTIVE RAS SIGNALING HAS BEEN SHOWN TO AUGMENT IL-2 PRODUCTION, REVERSE ANERGY, AND FUNCTIONALLY REPLACE MANY ASPECTS OF CD28 CO-STIMULATION IN CD4+ T CELLS. THESE DATA RAISE THE POSSIBILITY THAT INTRODUCTION OF ACTIVE RAS INTO PRIMARY T CELLS MIGHT RESULT IN IMPROVED FUNCTIONALITY IN PATHOLOGIC SITUATIONS OF T CELL DYSFUNCTION, SUCH AS CANCER OR CHRONIC VIRAL INFECTION. TO TEST THE BIOLOGIC EFFECTS OF ACTIVE RAS IN PRIMARY T CELLS, CD4+ T CELLS FROM COXSACKIE-ADENOVIRUS RECEPTOR TRANSGENIC MICE WERE TRANSDUCED WITH AN ADENOVIRUS ENCODING ACTIVE RAS. AS EXPECTED, ACTIVE RAS AUGMENTED IL-2 PRODUCTION IN NAIVE CD4+ T CELLS. HOWEVER, WHEN CELLS WERE CULTURED FOR 4 DAYS UNDER CONDITIONS TO PROMOTE EFFECTOR CELL DIFFERENTIATION, ACTIVE RAS INHIBITED THE ABILITY OF CD4+ T CELLS TO ACQUIRE A TH1 OR TH2 EFFECTOR CYTOKINE PROFILE. THIS DIFFERENTIATION DEFECT WAS NOT DUE TO DEFICIENT STAT4 OR STAT6 ACTIVATION BY IL-12 OR IL-4, RESPECTIVELY, NOR WAS IT ASSOCIATED WITH DEFICIENT INDUCTION OF T-BET AND GATA-3 EXPRESSION. IMPAIRED EFFECTOR CYTOKINE PRODUCTION IN ACTIVE RAS-TRANSDUCED CELLS WAS ASSOCIATED WITH DEFICIENT DEMETHYLATION OF THE IL-4 GENE LOCUS. OUR RESULTS INDICATE THAT, DESPITE AUGMENTING ACUTE ACTIVATION OF NAIVE T CELLS, CONSTITUTIVE RAS SIGNALING INHIBITS THE ABILITY OF CD4+ T CELLS TO PROPERLY DIFFERENTIATE INTO TH1/TH2 EFFECTOR CYTOKINE-PRODUCING CELLS, IN PART BY INTERFERING WITH EPIGENETIC MODIFICATION OF EFFECTOR GENE LOCI. ALTERNATIVE STRATEGIES TO POTENTIATE RAS PATHWAY SIGNALING IN T CELLS IN A MORE REGULATED FASHION SHOULD BE CONSIDERED AS A THERAPEUTIC APPROACH TO IMPROVE IMMUNE RESPONSES IN VIVO. 2014 15 1036 30 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 16 6910 20 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 17 3946 34 LNCRNA MALAT1 BINDS CHROMATIN REMODELING SUBUNIT BRG1 TO EPIGENETICALLY PROMOTE INFLAMMATION-RELATED HEPATOCELLULAR CARCINOMA PROGRESSION. HEPATOCELLULAR CARCINOMA (HCC) IS ONE TYPE OF CANCERS WHOSE CARCINOGENESIS AND PROGRESSION ARE CLOSELY RELATED TO CHRONIC INFLAMMATION. IDENTIFYING THE MOLECULAR MECHANISMS FOR INFLAMMATION-RELATED HCC PROGRESSION WILL CONTRIBUTE TO IMPROVE THE EFFICACY OF CURRENT THERAPEUTICS FOR HCC PATIENTS. MANY KINDS OF EPIGENETIC FACTORS, INCLUDING LONG NON-CODING RNAS (LNCRNAS), HAVE BEEN DISCOVERED TO BE IMPORTANT IN HCC GROWTH AND METASTASIS. HOWEVER, HOW THE LNCRNAS PROMOTE HCC PROGRESSION AND WHAT'S THE APPLICATION OF LNCRNA SILENCING IN VIVO IN SUPPRESSING HCC REMAIN TO BE FURTHER INVESTIGATED. HERE, WE FOUND THAT LNCRNA METASTASIS ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT1 (MALAT1) WAS UPREGULATED IN HCC TUMOR TISSUES, AND KNOCKDOWN OF MALAT1 SUPPRESSED PROLIFERATION, CELL CYCLE AND INVASION OF HCC CELLS IN RESPONSE TO LIPOPOLYSACCHARIDE (LPS) STIMULATION. KNOCKDOWN OF MALAT1 SIGNIFICANTLY INHIBITED LPS-INDUCED PRO-INFLAMMATORY MEDIATORS IL-6 AND CXCL8 EXPRESSION IN HCC CELLS, WHICH COULD BE RESTORED BY OVEREXPRESSING MALAT1. MECHANISTICALLY, MALAT1 RECRUITED BRAHMA-RELATED GENE 1 (BRG1), A CATALYTIC SUBUNIT OF CHROMATIN REMODELING COMPLEX SWITCHING/SUCROSE NON-FERMENTABLE (SWI/SNF), TO THE PROMOTER REGION OF IL-6 AND CXCL8, AND THUS FACILITATED NF-KAPPAB TO INDUCE THE EXPRESSION OF THESE INFLAMMATORY FACTORS. IMPORTANTLY, IN VIVO SILENCING OF MALAT1 IN HCC TISSUES INHIBITED GROWTH OF HCC XENOGRAFTS, AND ALSO SUPPRESSED THE EXPRESSION OF PRO-INFLAMMATORY FACTORS IN HCC TISSUES ACCORDINGLY. OUR RESULTS DEMONSTRATE THAT MALAT1 PROMOTES HCC PROGRESSION BY BINDING BRG1 TO EPIGENETICALLY ENHANCE INFLAMMATORY RESPONSE IN HCC TISSUES, AND SILENCING OF MALAT1 MAY BE A POTENTIAL APPROACH TO THE TREATMENT OF HCC. 2019 18 3276 27 HEPATOCYTE GROWTH CONTROL BY SOCS1 AND SOCS3. THE EXTRAORDINARY CAPACITY OF THE LIVER TO REGENERATE FOLLOWING INJURY IS DEPENDENT ON COORDINATED AND REGULATED ACTIONS OF CYTOKINES AND GROWTH FACTORS. WHEREAS HEPATOCYTE GROWTH FACTOR (HGF) AND EPIDERMAL GROWTH FACTOR (EGF) ARE DIRECT MITOGENS TO HEPATOCYTES, INFLAMMATORY CYTOKINES SUCH AS TNFALPHA AND IL-6 ALSO PLAY ESSENTIAL ROLES IN THE LIVER REGENERATION PROCESS. THESE CYTOKINES AND GROWTH FACTORS ACTIVATE DIFFERENT SIGNALING PATHWAYS IN A SEQUENTIAL MANNER TO ELICIT HEPATOCYTE PROLIFERATION. THE KINETICS AND MAGNITUDE OF THESE HEPATOCYTE-ACTIVATING STIMULI ARE TIGHTLY REGULATED TO ENSURE RESTORATION OF A FUNCTIONAL LIVER MASS WITHOUT CAUSING UNCONTROLLED CELL PROLIFERATION. HEPATOCYTE PROLIFERATION CAN BECOME DEREGULATED UNDER CONDITIONS OF CHRONIC INFLAMMATION, LEADING TO ACCUMULATION OF GENETIC ABERRATIONS AND EVENTUAL NEOPLASTIC TRANSFORMATION. AMONG THE CONTROL MECHANISMS THAT REGULATE HEPATOCYTE PROLIFERATION, NEGATIVE FEEDBACK INHIBITION BY THE 'SUPPRESSOR OF CYTOKINE SIGNALING (SOCS)' FAMILY PROTEINS SOCS1 AND SOCS3 PLAY CRUCIAL ROLES IN ATTENUATING CYTOKINE AND GROWTH FACTOR SIGNALING. LOSS OF SOCS1 OR SOCS3 IN THE MOUSE LIVER INCREASES THE RATE OF LIVER REGENERATION AND RENDERS HEPATOCYTES SUSCEPTIBLE TO NEOPLASTIC TRANSFORMATION. THE FREQUENT EPIGENETIC REPRESSION OF THE SOCS1 AND SOCS3 GENES IN HEPATOCELLULAR CARCINOMA HAS STIMULATED RESEARCH IN UNDERSTANDING THE GROWTH REGULATORY MECHANISMS OF SOCS1 AND SOCS3 IN HEPATOCYTES. WHEREAS SOCS3 IS IMPLICATED IN REGULATING JAK-STAT SIGNALING INDUCED BY IL-6 AND ATTENUATING EGFR SIGNALING, SOCS1 IS CRUCIAL FOR THE REGULATION OF HGF SIGNALING. THESE TWO PROTEINS ALSO MODULE THE FUNCTIONS OF CERTAIN KEY PROTEINS THAT CONTROL THE CELL CYCLE. IN THIS REVIEW, WE DISCUSS THE CURRENT UNDERSTANDING OF THE FUNCTIONS OF SOCS1 AND SOCS3 IN CONTROLLING HEPATOCYTE PROLIFERATION, AND ITS IMPLICATIONS TO LIVER HEALTH AND DISEASE. 2019 19 3217 37 HEDGEHOG/GLI AND PI3K SIGNALING IN THE INITIATION AND MAINTENANCE OF CHRONIC LYMPHOCYTIC LEUKEMIA. THE INITIATION AND MAINTENANCE OF A MALIGNANT PHENOTYPE REQUIRES COMPLEX AND SYNERGISTIC INTERACTIONS OF MULTIPLE ONCOGENIC SIGNALS. THE HEDGEHOG (HH)/GLI PATHWAY HAS BEEN IMPLICATED IN A VARIETY OF CANCER ENTITIES AND TARGETED PATHWAY INHIBITION IS OF THERAPEUTIC RELEVANCE. SIGNAL CROSS-TALK WITH OTHER CANCER PATHWAYS INCLUDING PI3K/AKT MODULATES HH/GLI SIGNAL STRENGTH AND ITS ONCOGENICITY. IN THIS STUDY, WE ADDRESSED THE ROLE OF HH/GLI AND ITS PUTATIVE INTERACTION WITH THE PI3K/AKT CASCADE IN THE INITIATION AND MAINTENANCE OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). USING TRANSGENIC MOUSE MODELS, WE SHOW THAT B-CELL-SPECIFIC CONSTITUTIVE ACTIVATION OF HH/GLI SIGNALING EITHER AT THE LEVEL OF THE HH EFFECTOR AND DRUG TARGET SMOOTHENED OR AT THE LEVEL OF THE GLI TRANSCRIPTION FACTORS DOES NOT SUFFICE TO INITIATE A CLL-LIKE PHENOTYPE CHARACTERIZED BY THE ACCUMULATION OF CD5(+) B CELLS IN THE LYMPHATIC SYSTEM AND PERIPHERAL BLOOD. FURTHERMORE, HH/GLI ACTIVATION IN PTEN-DEFICIENT B CELLS WITH ACTIVATED PI3K/AKT SIGNALING FAILED TO ENHANCE THE EXPANSION OF LEUKEMIC CD5(+) B CELLS, SUGGESTING THAT GENETIC OR EPIGENETIC ALTERATIONS LEADING TO ABERRANT HH/GLI SIGNALING IN B CELLS DO NOT SUFFICE TO ELICIT A CLL-LIKE PHENOTYPE IN MICE. BY CONTRAST, WE IDENTIFY A CRITICAL ROLE OF GLI AND PI3K SIGNALING FOR THE SURVIVAL OF HUMAN PRIMARY CLL CELLS. WE SHOW THAT COMBINED TARGETING OF GLI AND PI3K/AKT/MTOR SIGNALING CAN HAVE A SYNERGISTIC THERAPEUTIC EFFECT IN CELLS FROM A SUBGROUP OF CLL PATIENTS, THEREBY PROVIDING A BASIS FOR THE EVALUATION OF FUTURE COMBINATION THERAPIES TARGETING HH/GLI AND PI3K SIGNALING IN THIS COMMON HEMATOPOIETIC MALIGNANCY. 2015 20 3864 29 JAK-STAT PATHWAY INHIBITION PARTIALLY RESTORES INTESTINAL HOMEOSTASIS IN HDAC1- AND HDAC2-INTESTINAL EPITHELIAL CELL-DEFICIENT MICE. WE HAVE PREVIOUSLY REPORTED THAT HISTONE DEACETYLASE EPIGENETIC REGULATOR HDAC1 AND HDAC2 DELETION IN INTESTINAL EPITHELIAL CELLS (IEC) DISRUPTS MUCOSAL TISSUE ARCHITECTURE AND BARRIER, CAUSING CHRONIC INFLAMMATION. IN THIS STUDY, PROTEOME AND TRANSCRIPTOME ANALYSIS REVEALED THE IMPORTANCE OF SIGNALING PATHWAYS INDUCED UPON GENETIC IEC-HDAC1 AND HDAC2 DELETION. INDEED, GENE ONTOLOGY BIOLOGICAL PROCESS ANALYSIS OF ENRICHED DEFICIENT IEC RNA AND PROTEINS IDENTIFIED COMMON PATHWAYS, INCLUDING LIPID METABOLIC AND OXIDATION-REDUCTION PROCESS, CELL ADHESION, AND ANTIGEN PROCESSING AND PRESENTATION, RELATED TO IMMUNE RESPONSES, CORRELATING WITH DYSREGULATION OF MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS II GENES. TOP UPSTREAM REGULATORS INCLUDED REGULATORS ASSOCIATED WITH ENVIRONMENTAL SENSING PATHWAYS TO XENOBIOTICS, MICROBIAL AND DIET-DERIVED LIGANDS, AND ENDOGENOUS METABOLITES. PROTEOME ANALYSIS REVEALED MTOR SIGNALING IEC-SPECIFIC DEFECTS. IN ADDITION TO MTOR, THE STAT AND NOTCH PATHWAYS WERE DYSREGULATED SPECIFICALLY IN JEJUNAL IEC. TO DETERMINE THE IMPACT OF PATHWAY DYSREGULATION ON MUTANT JEJUNUM ALTERATIONS, WE TREATED MUTANT MICE WITH TOFACITINIB, A JAK INHIBITOR. TREATMENT WITH THE INHIBITOR PARTIALLY CORRECTED PROLIFERATION AND TIGHT JUNCTION DEFECTS, AS WELL AS NICHE STABILIZATION BY INCREASING PANETH CELL NUMBERS. THUS, IEC-SPECIFIC HISTONE DEACETYLASES 1 (HDAC1) AND 2 (HDAC2) SUPPORT INTESTINAL HOMEOSTASIS BY REGULATING SURVIVAL AND TRANSLATION PROCESSES, AS WELL AS DIFFERENTIATION AND METABOLIC PATHWAYS. HDAC1 AND HDAC2 MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF IEC-SPECIFIC INFLAMMATORY RESPONSES BY CONTROLLING, DIRECTLY OR INDIRECTLY, THE JAK/STAT PATHWAY. IEC-SPECIFIC JAK/STAT PATHWAY DEREGULATION MAY BE, AT LEAST IN PART, RESPONSIBLE FOR INTESTINAL HOMEOSTASIS DISRUPTION IN MUTANT MICE. 2021