1 2451 107 EPIGENETIC SUPPRESSION OF PGC1ALPHA (PPARGC1A) CAUSES COLLATERAL SENSITIVITY TO HMGCR-INHIBITORS WITHIN BRAF-TREATMENT RESISTANT MELANOMAS. WHILE TARGETED TREATMENT AGAINST BRAF(V600E) IMPROVE SURVIVAL FOR MELANOMA PATIENTS, MANY WILL SEE THEIR CANCER RECUR. HERE WE PROVIDE DATA INDICATING THAT EPIGENETIC SUPPRESSION OF PGC1ALPHA DEFINES AN AGGRESSIVE SUBSET OF CHRONIC BRAF-INHIBITOR TREATED MELANOMAS. A METABOLISM-CENTERED PHARMACOLOGICAL SCREEN FURTHER IDENTIFIES STATINS (HMGCR INHIBITORS) AS A COLLATERAL VULNERABILITY WITHIN PGC1ALPHA-SUPPRESSED BRAF-INHIBITOR RESISTANT MELANOMAS. LOWER PGC1ALPHA LEVELS MECHANISTICALLY CAUSES REDUCED RAB6B AND RAB27A EXPRESSION, WHEREBY THEIR COMBINED RE-EXPRESSION REVERSES STATIN VULNERABILITY. BRAF-INHIBITOR RESISTANT CELLS WITH REDUCED PGC1ALPHA HAVE INCREASED INTEGRIN-FAK SIGNALING AND IMPROVED EXTRACELLULAR MATRIX DETACHED SURVIVAL CUES THAT HELPS EXPLAIN THEIR INCREASED METASTATIC ABILITY. STATIN TREATMENT BLOCKS CELL GROWTH BY LOWERING RAB6B AND RAB27A PRENYLATION THAT REDUCES THEIR MEMBRANE ASSOCIATION AND AFFECTS INTEGRIN LOCALIZATION AND DOWNSTREAM SIGNALING REQUIRED FOR GROWTH. THESE RESULTS SUGGEST THAT CHRONIC ADAPTATION TO BRAF-TARGETED TREATMENTS DRIVE NOVEL COLLATERAL METABOLIC VULNERABILITIES, AND THAT HMGCR INHIBITORS MAY OFFER A STRATEGY TO TREAT MELANOMAS RECURRING WITH SUPPRESSED PGC1ALPHA EXPRESSION. 2023 2 2057 18 EPIGENETIC CONTROL OF EPILEPSY TARGET GENES CONTRIBUTES TO A CELLULAR MEMORY OF EPILEPTOGENESIS IN CULTURED RAT HIPPOCAMPAL NEURONS. HYPERSYNCHRONOUS NEURONAL EXCITATION MANIFESTS CLINICALLY AS SEIZURE (ICTOGENESIS), AND MAY RECUR SPONTANEOUSLY AND REPETITIVELY AFTER A VARIABLE LATENCY PERIOD (EPILEPTOGENESIS). DESPITE TREMENDOUS RESEARCH EFFORTS TO DESCRIBE MOLECULAR PATHWAYS AND SIGNATURES OF EPILEPTOGENESIS, MOLECULAR PATHOMECHANISMS LEADING TO CHRONIC EPILEPSY REMAIN TO BE CLARIFIED. WE HYPOTHESIZED THAT EPIGENETIC MODIFICATIONS MAY FORM THE BASIS FOR A CELLULAR MEMORY OF EPILEPTOGENESIS, AND USED A PRIMARY NEURONAL CELL CULTURE MODEL OF THE RAT HIPPOCAMPUS TO STUDY THE TRANSLATION OF MASSIVE NEURONAL EXCITATION INTO PERSISTING CHANGES OF EPIGENETIC SIGNATURES AND PRO-EPILEPTOGENIC TARGET GENE EXPRESSION. INCREASED SPONTANEOUS ACTIVATION OF CULTURED NEURONS WAS DETECTED 3 AND 7 DAYS AFTER STIMULATION WITH 10 MUM GLUTAMATE WHEN COMPARED TO SHAM-TREATED TIME-MATCHED CONTROLS USING CALCIUM-IMAGING IN VITRO. CHROMATIN-IMMUNOPRECIPITATION EXPERIMENTS REVEALED SHORT-TERM (3 H, 7 H, AND 24 H) AND LONG-TERM (3 D AND 2 WEEKS) CHANGES IN HISTONE MODIFICATIONS, WHICH WERE DIRECTLY LINKED TO DECREASED EXPRESSION OF TWO SELECTED EPILEPSY TARGET GENES, E.G. EXCITATORY GLUTAMATE RECEPTOR GENES GRIA2 AND GRIN2A. INCREASED PROMOTER METHYLATION OBSERVED 4 WEEKS AFTER GLUTAMATE STIMULATION AT RESPECTIVE GENES SUGGESTED LONG-TERM REPRESSION OF GRIA2 AND GRIN2A GENES. INHIBITION OF GLUTAMATERGIC ACTIVATION OR BLOCKING THE PROPAGATION OF ACTION POTENTIALS IN CULTURED NEURONS RESCUED ALTERED GENE EXPRESSION AND REGULATORY EPIGENETIC MODIFICATIONS. OUR DATA SUPPORT THE CONCEPT OF A CELLULAR MEMORY OF EPILEPTOGENESIS AND PERSISTING EPIGENETIC MODIFICATIONS OF EPILEPSY TARGET GENES, WHICH ARE ABLE TO TURN NORMAL INTO PRO-EPILEPTIC NEURONS AND CIRCUITS. 2017 3 4885 21 OVERVIEW ON MOLECULAR BIOMARKERS FOR LARYNGEAL CANCER: LOOKING FOR NEW ANSWERS TO AN OLD PROBLEM. LARYNGEAL SQUAMOUS CELL CANCER (LSCC) ACCOUNTS FOR ALMOST 25-30% OF ALL HEAD AND NECK SQUAMOUS CELL CANCERS AND IS CLUSTERED ACCORDING TO THE AFFECTED DISTRICTS, AS THIS DETERMINES DISTINCT TENDENCY TO RECUR AND METASTASIZE. A MAJOR ROLE FOR NUMEROUS GENETIC ALTERATIONS IN DRIVING THE ONSET AND PROGRESSION OF THIS NEOPLASM IS EMERGING. HOWEVER, MAJOR EFFORTS ARE STILL REQUIRED FOR THE IDENTIFICATION OF MOLECULAR MARKERS USEFUL FOR BOTH EARLY DIAGNOSIS AND PROGNOSTIC DEFINITION OF LSCC THAT IS STILL CHARACTERIZED BY SIGNIFICANT MORBIDITY AND MORTALITY. NON-CODING RNAS APPEAR THE MOST PROMISING AS THEY CIRCULATE IN ALL THE BIOLOGICAL FLUIDS ALLOWING LIQUID BIOPSY DETERMINATION, AS WELL AS DUE TO THEIR QUICK AND CHARACTERISTIC MODULATION USEFUL FOR NON-INVASIVE DETECTION AND MONITORING OF CANCER. OTHER CRITICAL ASPECTS ARE RELATED TO RECENT PROGRESS IN CIRCULATING TUMOR CELLS AND DNA DETECTION, IN METASTATIC STATUS AND CHEMO-REFRACTORINESS PREDICTION, AND IN THE FUNCTIONAL INTERACTION OF LSCC WITH CHRONIC INFLAMMATION AND INNATE IMMUNITY. WE REVIEW ALL THESE ASPECTS TAKING INTO ACCOUNT THE PROGRESS OF THE TECHNOLOGIES IN THE FIELD OF NEXT GENERATION SEQUENCING. 2022 4 5535 18 ROLE OF BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS IN RELAPSE TO COCAINE-SEEKING BEHAVIOR IN MICE. COCAINE ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER CHARACTERIZED BY COMPULSIVE DRUG SEEKING. PRELIMINARY STUDY SUGGESTED THAT BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC READER PROTEIN, PARTICIPATES IN COCAINE-INDUCED REWARD AND NEUROPLASTICITY. HOWEVER, THE EXACT ROLE OF BRD4 IN COCAINE ADDICTION, PARTICULARLY COCAINE RELAPSE, REMAINS ELUSIVE. IN THIS STUDY, WE FOUND THAT BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS (NAC) WAS CLOSELY RELATED TO THE MAINTENANCE OF COCAINE REINFORCEMENT AND RELAPSE IN DIFFERENT COCAINE EXPOSURE PARADIGMS. COCAINE SIGNIFICANTLY INCREASED THE BINDING OF PHOSPHORYLATED BRD4 (PBRD4) AT THE PROMOTER OF GRIA2 AND BDNF GENES IN THE NAC. (+)JQ1, A SELECTIVE BRD4 INHIBITOR, MARKEDLY REDUCED THE REINFORCEMENT AND REINSTATEMENT OF COCAINE-SEEKING BEHAVIORS, WHICH WAS ACCOMPANIED BY THE DECREASED EXPRESSIONS OF GRIA2 AND BDNF. FURTHERMORE, CHROMATIN IMMUNOPRECIPITATION ASSAY SHOWED THAT (+)JQ1 CLEARLY ATTENUATED COCAINE-ENHANCED BINDING OF PBRD4 AT THE PROMOTOR OF GRIA2 AND BDNF GENES. BLOCKADE OF CASEIN KINASE II SIGNIFICANTLY ATTENUATED BRD4 PHOSPHORYLATION AND COCAINE RELAPSE-LIKE BEHAVIORS, SUGGESTING THE IMPORTANT ROLE OF PBRD4 IN MODULATING COCAINE EFFECT. TOGETHER, OUR FINDINGS SUGGEST THAT BRD4 PHOSPHORYLATION IN THE NAC MODULATES MULTIPLE ADDICTION-RELATED BEHAVIORS OF COCAINE AND PARTICULARLY RELAPSE TO COCAINE-SEEKING BEHAVIORS. INHIBITION OF BRD4 ACTIVITY MAY BE A NOVEL TARGET AGAINST COCAINE ADDICTION AND RELAPSE. 2020 5 142 27 ABERRANT DNA METHYLATION OF PHOSPHODIESTERASE [CORRECTED] 4D ALTERS AIRWAY SMOOTH MUSCLE CELL PHENOTYPES. AIRWAY HYPERRESPONSIVENESS (AHR) IS A HALLMARK FEATURE IN ASTHMA CHARACTERIZED BY EXAGGERATED AIRWAY CONTRACTILE RESPONSE TO STIMULI DUE TO INCREASED AIRWAY SENSITIVITY AND CHRONIC AIRWAY REMODELING. WE HAVE PREVIOUSLY SHOWN THAT ALLERGEN-INDUCED AHR IN MICE IS ASSOCIATED WITH ABERRANT DNA METHYLATION IN THE LUNG GENOME, SUGGESTING THAT AHR COULD BE EPIGENETICALLY REGULATED, AND THESE CHANGES MIGHT PREDISPOSE THE ANIMALS TO ASTHMA. PREVIOUS STUDIES DEMONSTRATED THAT OVEREXPRESSION OF PHOSPHODIESTERASE 4D (PDE4D) IS ASSOCIATED WITH INCREASED AHR. HOWEVER, EPIGENETIC REGULATION OF THIS GENE IN ASTHMATIC AIRWAY SMOOTH MUSCLE CELLS (ASMCS) HAS NOT BEEN EXAMINED. IN THIS STUDY, WE AIMED TO EXAMINE THE RELATIONSHIP BETWEEN EPIGENETIC REGULATION OF PDE4D AND ASMC PHENOTYPES. WE IDENTIFIED CPG SITE-SPECIFIC HYPOMETHYLATION AT PDE4D PROMOTER IN HUMAN ASTHMATIC ASMCS. WE NEXT USED METHYLATED OLIGONUCLEOTIDES TO INTRODUCE CPG SITE-SPECIFIC METHYLATION AT PDE4D PROMOTER AND EXAMINED ITS EFFECT ON ASMCS. WE SHOWED THAT PDE4D METHYLATION DECREASED CELL PROLIFERATION AND MIGRATION OF ASTHMATIC ASMCS. WE FURTHER ELUCIDATED THAT METHYLATED PDE4D DECREASED PDE4D EXPRESSION IN ASTHMATIC ASMCS, INCREASED CAMP LEVEL, AND INHIBITED THE ABERRANT INCREASE IN CA(2+) LEVEL. MOREOVER, PDE4D METHYLATION REDUCED THE PHOSPHORYLATION LEVEL OF DOWNSTREAM EFFECTORS OF CA(2+) SIGNALING, INCLUDING MYOSIN LIGHT CHAIN KINASE AND P38. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE THAT GENE-SPECIFIC EPIGENETIC CHANGES MAY PREDISPOSE ASMCS TO ASTHMA THROUGH ALTERATIONS IN CELL PHENOTYPES. MODULATION OF ASMC PHENOTYPES BY METHYLATED PDE4D OLIGONUCLEOTIDES CAN REVERSE THE ABERRANT ASMC FUNCTIONS TO NORMAL PHENOTYPES. THIS HAS PROVIDED NEW INSIGHT TO THE DEVELOPMENT OF NOVEL THERAPEUTIC OPTIONS FOR THIS DEBILITATIVE DISEASE. 2016 6 581 27 BEHAVIORAL AND NEUROCHEMICAL CHARACTERIZATION OF TRKB-DEPENDENT MECHANISMS OF AGOMELATINE IN GLUCOCORTICOID RECEPTOR-IMPAIRED MICE. GROWING EVIDENCE INDICATES THAT IMPAIRMENT OF THE STRESS RESPONSE, IN PARTICULAR THE NEGATIVE FEEDBACK REGULATION MECHANISM EXERTED BY THE HYPOTHALAMO-PITUITARY-ADRENAL (HPA) AXIS, MIGHT BE RESPONSIBLE FOR THE HIPPOCAMPAL ATROPHY OBSERVED IN DEPRESSED PATIENTS. ANTIDEPRESSANTS, POSSIBLY THROUGH THE ACTIVATION OF BDNF SIGNALING, MAY ENHANCE NEUROPLASTICITY AND RESTORE NORMAL HIPPOCAMPAL FUNCTIONS. IN THIS CONTEXT, GLUCOCORTICOID RECEPTOR-IMPAIRED (GR-I) MICE-A TRANSGENIC MOUSE MODEL OF REDUCED GR-INDUCED NEGATIVE FEEDBACK REGULATION OF THE HPA AXIS-WERE USED TO INVESTIGATE THE ROLE OF BDNF/TRKB SIGNALING IN THE BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF THE NEW GENERATION ANTIDEPRESSANT DRUG, AGOMELATINE. GR-I MICE EXHIBITED MARKED ALTERATIONS IN DEPRESSIVE-LIKE AND ANXIETY-LIKE BEHAVIORS, TOGETHER WITH A DECREASED CELL PROLIFERATION AND ALTERED LEVELS OF NEUROPLASTIC AND EPIGENETIC MARKERS IN THE HIPPOCAMPUS. GR-I MICE AND THEIR WILD-TYPE LITTERMATES WERE TREATED FOR 21 DAYS WITH VEHICLE, AGOMELATINE (50MG/KG/DAY; I.P) OR THE TRKB INHIBITOR ANA-12 (0.5MG/KG/DAY, I.P) ALONE, OR IN COMBINATION WITH AGOMELATINE. CHRONIC TREATMENT WITH AGOMELATINE RESULTED IN ANTIDEPRESSANT-LIKE EFFECTS IN GR-I MICE AND REVERSED THE DEFICIT IN HIPPOCAMPAL CELL PROLIFERATION AND SOME OF THE ALTERATIONS OF MRNA PLASTICITY MARKERS IN GR-I MICE. ANA-12 BLOCKED THE EFFECT OF AGOMELATINE ON MOTOR ACTIVITY AS WELL AS ITS ABILITY TO RESTORE A NORMAL HIPPOCAMPAL CELL PROLIFERATION AND EXPRESSION OF NEUROTROPHIC FACTORS. ALTOGETHER, OUR FINDINGS INDICATE THAT AGOMELATINE REQUIRES TRKB SIGNALING TO REVERSE SOME OF THE MOLECULAR AND BEHAVIORAL ALTERATIONS CAUSED BY HPA AXIS IMPAIRMENT. 2016 7 3192 23 HDAC INHIBITION COUNTERACTS METASTATIC RE-ACTIVATION OF PROSTATE CANCER CELLS INDUCED BY CHRONIC MTOR SUPPRESSION. THIS STUDY WAS DESIGNED TO INVESTIGATE WHETHER EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITION MIGHT CIRCUMVENT RESISTANCE TOWARDS THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR) INHIBITOR TEMSIROLIMUS IN A PROSTATE CANCER CELL MODEL. PARENTAL (PAR) AND TEMSIROLIMUS-RESISTANT (RES) PC3 PROSTATE CANCER CELLS WERE EXPOSED TO THE HDAC INHIBITOR VALPROIC ACID (VPA), AND TUMOR CELL ADHESION, CHEMOTAXIS, MIGRATION, AND INVASION WERE EVALUATED. TEMSIROLIMUS RESISTANCE WAS CHARACTERIZED BY REDUCED BINDING OF PC3(RES) CELLS TO ENDOTHELIUM, IMMOBILIZED COLLAGEN, AND FIBRONECTIN, BUT INCREASED ADHESION TO LAMININ, AS COMPARED TO THE PARENTAL CELLS. CHEMOTAXIS, MIGRATION, AND INVASION OF PC3(RES) CELLS WERE ENHANCED FOLLOWING TEMSIROLIMUS RE-TREATMENT. INTEGRIN ALPHA AND BETA RECEPTORS WERE SIGNIFICANTLY ALTERED IN PC3(RES) COMPARED TO PC3(PAR) CELLS. VPA SIGNIFICANTLY COUNTERACTED TEMSIROLIMUS RESISTANCE BY DOWN-REGULATING TUMOR CELL(-)MATRIX INTERACTION, CHEMOTAXIS, AND MIGRATION. EVALUATION OF INTEGRIN EXPRESSION IN THE PRESENCE OF VPA REVEALED A SIGNIFICANT DOWN-REGULATION OF INTEGRIN ALPHA5 IN PC3(RES) CELLS. BLOCKING STUDIES DEMONSTRATED A CLOSE ASSOCIATION BETWEEN ALPHA5 EXPRESSION ON PC3(RES) AND CHEMOTAXIS. IN THIS IN VITRO MODEL, TEMSIROLIMUS RESISTANCE DROVE PROSTATE CANCER CELLS TO BECOME HIGHLY MOTILE, WHILE HDAC INHIBITION REVERSED THE METASTATIC ACTIVITY. THE VPA-INDUCED INHIBITION OF METASTATIC ACTIVITY WAS ACCOMPANIED BY A LOWERED INTEGRIN ALPHA5 SURFACE LEVEL ON THE TUMOR CELLS. 2018 8 2116 25 EPIGENETIC HISTONE DEACETYLATION INHIBITION PREVENTS THE DEVELOPMENT AND PERSISTENCE OF TEMPORAL LOBE EPILEPSY. EPILEPSY IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY REPEATED UNPROVOKED SEIZURES. CURRENTLY, NO DRUG THERAPY EXISTS FOR CURING EPILEPSY OR DISEASE MODIFICATION IN PEOPLE AT RISK. DESPITE SEVERAL EMERGING MECHANISMS, THERE HAVE BEEN FEW STUDIES OF EPIGENETIC SIGNALING IN EPILEPTOGENESIS, THE PROCESS WHEREBY A NORMAL BRAIN BECOMES PROGRESSIVELY EPILEPTIC BECAUSE OF PRECIPITATING FACTORS. HERE, WE REPORT A NOVEL ROLE OF HISTONE DEACETYLATION AS A CRITICAL EPIGENETIC MECHANISM IN EPILEPTOGENESIS. EXPERIMENTS WERE CONDUCTED USING THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE IN THE HIPPOCAMPUS KINDLING MODEL OF TEMPORAL LOBE EPILEPSY (TLE), A CLASSIC MODEL HEAVILY USED TO APPROVE DRUGS FOR TREATMENT OF EPILEPSY. DAILY TREATMENT WITH BUTYRATE SIGNIFICANTLY INHIBITED HDAC ACTIVITY AND RETARDED THE DEVELOPMENT OF LIMBIC EPILEPTOGENESIS WITHOUT AFFECTING AFTER-DISCHARGE SIGNAL. HDAC INHIBITION MARKEDLY IMPAIRED THE PERSISTENCE OF SEIZURE EXPRESSION MANY WEEKS AFTER EPILEPSY DEVELOPMENT. MOREOVER, SUBCHRONIC HDAC INHIBITION FOR 2 WEEKS RESULTED IN A STRIKING RETARDATION OF EPILEPTOGENESIS. HDAC INHIBITION, UNEXPECTEDLY, ALSO SHOWED ERASURE OF THE EPILEPTOGENIC STATE IN EPILEPTIC ANIMALS. FINALLY, BUTYRATE-TREATED ANIMALS EXHIBITED A POWERFUL REDUCTION IN MOSSY FIBER SPROUTING, A MORPHOLOGIC INDEX OF EPILEPTOGENESIS. TOGETHER THESE RESULTS UNDERSCORE THAT HDAC INHIBITION PREVENTS THE DEVELOPMENT OF TLE, INDICATING HDAC'S CRITICAL SIGNALING ROLE IN EPILEPTOGENESIS. THESE FINDINGS, THEREFORE, ENVISAGE A UNIQUE NOVEL THERAPY FOR PREVENTING OR CURING EPILEPSY BY TARGETING THE EPIGENETIC HDAC PATHWAY. 2018 9 5064 23 PHOSPHORYLATION OF RELA/P65 PROMOTES DNMT-1 RECRUITMENT TO CHROMATIN AND REPRESSES TRANSCRIPTION OF THE TUMOR METASTASIS SUPPRESSOR GENE BRMS1. THE MAJORITY OF PATIENTS WITH LUNG CANCER PRESENT WITH METASTATIC DISEASE. CHRONIC INFLAMMATION AND SUBSEQUENT ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) HAVE BEEN ASSOCIATED WITH THE DEVELOPMENT OF CANCERS. THE RELA/P65 SUBUNIT OF NF-KAPPAB IS TYPICALLY ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. IN THIS REPORT WE SHOW THAT RELA/P65 CAN FUNCTION AS AN ACTIVE TRANSCRIPTIONAL REPRESSOR THROUGH ENHANCED METHYLATION OF THE BRMS1 (BREAST CANCER METASTASIS SUPPRESSOR 1) METASTASIS SUPPRESSOR GENE PROMOTER VIA DIRECT RECRUITMENT OF DNMT-1 (DNA (CYTOSINE-5)-METHYLTRANSFERASE 1) TO CHROMATIN IN RESPONSE TO TUMOR NECROSIS FACTOR (TNF). TNF-MEDIATED PHOSPHORYLATION OF S276 ON RELA/P65 IS REQUIRED FOR RELA/P65-DNMT-1 INTERACTIONS, CHROMATIN LOADING OF DNMT-1 AND SUBSEQUENT BRMS1 PROMOTER METHYLATION AND TRANSCRIPTIONAL REPRESSION. THE ABILITY OF RELA/P65 TO FUNCTION AS AN ACTIVE TRANSCRIPTIONAL REPRESSOR IS PROMOTER SPECIFIC, AS THE NF-KAPPAB-REGULATED GENE CIAP2 (CELLULAR INHIBITOR OF APOPTOSIS 2) IS TRANSCRIPTIONALLY ACTIVATED WHEREAS BRMS1 IS REPRESSED UNDER IDENTICAL CONDITIONS. SMALL-MOLECULE INHIBITION OF EITHER OF THE MINIMAL INTERACTING DOMAINS BETWEEN RELA/P65-DNMT-1 AND RELA/P65-BRMS1 PROMOTER ABROGATES BRMS1 METHYLATION AND ITS TRANSCRIPTIONAL REPRESSION. THE ABILITY OF RELA/P65 TO DIRECTLY RECRUIT DNMT-1 TO CHROMATIN, RESULTING IN PROMOTER-SPECIFIC METHYLATION AND TRANSCRIPTIONAL REPRESSION OF TUMOR METASTASIS SUPPRESSOR GENE BRMS1, HIGHLIGHTS A NEW MECHANISM THROUGH WHICH NF-KAPPAB CAN REGULATE METASTATIC DISEASE, AND OFFERS A POTENTIAL TARGET FOR NEWER-GENERATION EPIGENETIC ONCOPHARMACEUTICALS. 2012 10 237 22 ADENOSINE AUGMENTATION EVOKED BY AN ENT1 INHIBITOR IMPROVES MEMORY IMPAIRMENT AND NEURONAL PLASTICITY IN THE APP/PS1 MOUSE MODEL OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A NEURODEGENERATIVE DISORDER CHARACTERIZED BY COGNITIVE IMPAIRMENT AND SYNAPTIC DYSFUNCTION. ADENOSINE IS AN IMPORTANT HOMEOSTATIC MODULATOR THAT CONTROLS THE BIOENERGETIC NETWORK IN THE BRAIN THROUGH REGULATING RECEPTOR-EVOKED SIGNALING PATHWAYS, BIOENERGETIC MACHINERIES, AND EPIGENETIC-MEDIATED GENE REGULATION. EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 (ENT1) IS A MAJOR ADENOSINE TRANSPORTER THAT RECYCLES ADENOSINE FROM THE EXTRACELLULAR SPACE. IN THE PRESENT STUDY, WE REPORT THAT A SMALL ADENOSINE ANALOGUE (DESIGNATED J4) THAT INHIBITED ENT1 PREVENTED THE DECLINE IN SPATIAL MEMORY IN AN AD MOUSE MODEL (APP/PS1). ELECTROPHYSIOLOGICAL AND BIOCHEMICAL ANALYSES FURTHER DEMONSTRATED THAT CHRONIC TREATMENT WITH J4 NORMALIZED THE IMPAIRED BASAL SYNAPTIC TRANSMISSION AND LONG-TERM POTENTIATION (LTP) AT SCHAFFER COLLATERAL SYNAPSES AS WELL AS THE ABERRANT EXPRESSION OF SYNAPTIC PROTEINS (E.G., NR2A AND NR2B), ABNORMAL NEURONAL PLASTICITY-RELATED SIGNALING PATHWAYS (E.G., PKA AND GSK3BETA), AND DETRIMENTAL ELEVATION IN ASTROCYTIC A(2A)R EXPRESSION IN THE HIPPOCAMPUS AND CORTEX OF APP/PS1 MICE. IN CONCLUSION, OUR FINDINGS SUGGEST THAT MODULATION OF ADENOSINE HOMEOSTASIS BY J4 IS BENEFICIAL IN A MOUSE MODEL OF AD. OUR STUDY PROVIDES A POTENTIAL THERAPEUTIC STRATEGY TO DELAY THE PROGRESSION OF AD. 2018 11 532 18 ASTROCYTIC C-JUN N-TERMINAL KINASE-HISTONE DEACETYLASE-2 CASCADE CONTRIBUTES TO GLUTAMATE TRANSPORTER-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY IN RATS. DECREASE OF GLUTAMATE TRANSPORTER-1 (GLT-1) IN THE SPINAL DORSAL HORN AFTER NERVE INJURY INDUCES ENHANCED EXCITATORY TRANSMISSION AND CAUSES PERSISTENT PAIN. HISTONE DEACETYLASES (HDACS)-CATALYZED DEACETYLATION MIGHT CONTRIBUTE TO THE DECREASE OF GLT-1, WHILE THE DETAILED MECHANISMS HAVE YET TO BE FULLY ELABORATED. SPINAL NERVE LIGATION (SNL) INDUCED SIGNIFICANT INCREASES OF HDAC2 AND DECREASES OF GLT-1 IN SPINAL ASTROCYTES. INTRATHECAL INFUSION OF THE HDAC2 INHIBITORS ATTENUATED THE DECREASE OF GLT-1 AND ENHANCED PHOSPHORYLATION OF GLUTAMATE RECEPTORS. GLT-1 AND PHOSPHORYLATED C-JUN N-TERMINAL KINASE (JNK) WERE HIGHLY COLOCALIZED IN THE SPINAL CORD, AND A LARGE NUMBER OF PJNK POSITIVE CELLS WERE HDAC2 POSITIVE. INTRATHECALLY INFUSION OF THE JNK INHIBITOR SP600125 SIGNIFICANTLY INHIBITED SNL-INDUCED UPREGULATION OF HDAC2. SNL-INDUCED HDAC2 UP-REGULATION COULD BE INHIBITED BY THE NEUTRALIZING ANTI-TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) BINDING PROTEIN ETANERCEPT OR THE MICROGLIAL INHIBITOR MINOCYCLINE. IN CULTURED ASTROCYTES, TNF-ALPHA INDUCED ENHANCED PHOSPHORYLATION OF JNK AND A SIGNIFICANT INCREASE OF HDAC2, AS WELL AS A REMARKABLE DECREASE OF GLT-1, WHICH COULD BE PREVENTED BY SP600125 OR THE HDAC2 SPECIFIC INHIBITOR CAY10683. OUR DATA SUGGEST THAT ASTROCYTIC JNK-HDAC2 CASCADE CONTRIBUTES TO GLT-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY. NEUROIMMUNE ACTIVATION AFTER PERIPHERAL NERVE INJURY COULD INDUCE EPIGENETIC MODIFICATION CHANGES IN ASTROCYTES AND CONTRIBUTE TO CHRONIC PAIN MAINTENANCE. 2021 12 6077 25 THE EFFECT OF CD4 RECEPTOR DOWNREGULATION AND ITS DOWNSTREAM SIGNALING MOLECULES ON HIV-1 LATENCY. HIV-1 CAN ESTABLISH A LATENT INFECTION IN MEMORY CD4+T CELLS TO EVADE THE HOST IMMUNE RESPONSE. CD4 MOLECULES CAN ACT NOT ONLY AS THE HIV-1 RECEPTOR FOR ENTRY BUT ALSO AS THE TRIGGER IN AN INTRACELLULAR SIGNALING CASCADE FOR T-CELL ACTIVATION AND PROLIFERATION VIA PROTEIN TYROSINE KINASES. NOVEL CHRONIC HIV-1-INFECTED A3.01-DERIVED (NCHA) CELLS WERE USED TO EXAMINE THE INVOLVEMENT OF CD4 DOWNSTREAM SIGNALING IN HIV-1 LATENCY. CD4 RECEPTORS IN NCHA CELLS WERE DRAMATICALLY DOWNREGULATED ON ITS SURFACE BUT WERE SLIGHTLY DECREASED IN WHOLE-CELL LYSATES. THE EXPRESSION LEVELS OF CD4 DOWNSTREAM SIGNALING MOLECULES, INCLUDING P56(LCK), ZAP-70, LAT, AND C-JUN, WERE SHARPLY DECREASED IN NCHA CELLS. THE LOWERED HISTONE MODIFICATIONS OF H3K4ME3 AND H3K9AC CORRELATED WITH THE DOWNREGULATION OF P56(LCK), ZAP-70, AND LAT IN NCHA CELLS. AP-1 BINDING ACTIVITY WAS ALSO REDUCED IN NCHA CELLS. LAT AND C-JUN SUPPRESSED IN NCHA CELLS WERE HIGHLY INDUCED AFTER PMA TREATMENT. IN EPIGENETIC ANALYSIS, OTHER SIGNAL TRANSDUCTION MOLECULES WHICH ARE ASSOCIATED WITH ACTIVE AND/OR LATENT HIV-1 INFECTION SHOWED NORMAL STATES IN HIV-1 LATENTLY INFECTED CELLS COMPARED TO A3.01 CELLS. IN CONCLUSION, WE DEMONSTRATED THAT THE HIV-1 LATENT STATE IS SUSTAINED BY THE REDUCTION OF DOWNSTREAM SIGNALING MOLECULES VIA THE DOWNREGULATION OF CD4 AND THE ATTENUATED ACTIVITY OF TRANSCRIPTION FACTOR AS AP-1. THE HIV-1 LATENCY MODEL VIA T-CELL DEACTIVATION MAY PROVIDE SOME CLUES FOR THE DEVELOPMENT OF THE NEW ANTIRESERVOIR THERAPY. 2011 13 5617 26 SARCOSINE SUPPRESSES EPILEPTOGENESIS IN RATS WITH EFFECTS ON HIPPOCAMPAL DNA METHYLATION. EPILEPTOGENESIS IS A COMMON CONSEQUENCE OF BRAIN INSULTS, HOWEVER, THE PREVENTION OR DELAY OF THE EPILEPTOGENIC PROCESS REMAINS AN IMPORTANT UNMET MEDICAL CHALLENGE. OVEREXPRESSION OF GLYCINE TRANSPORTER 1 (GLYT1) IS PROPOSED AS A PATHOLOGICAL HALLMARK IN THE HIPPOCAMPUS OF PATIENTS WITH TEMPORAL LOBE EPILEPSY (TLE), AND WE PREVIOUSLY DEMONSTRATED IN RODENT EPILEPSY MODELS THAT AUGMENTATION OF GLYCINE SUPPRESSED CHRONIC SEIZURES AND ALTERED ACUTE SEIZURE THRESHOLDS. IN THE PRESENT STUDY WE EVALUATED THE EFFECT OF THE GLYT1 INHIBITOR, SARCOSINE (AKA N-METHYLGLYCINE), ON EPILEPTOGENESIS AND ALSO INVESTIGATED POSSIBLE MECHANISMS. WE DEVELOPED A MODIFIED RAPID KINDLING MODEL OF EPILEPTOGENESIS IN RATS COMBINED WITH SEIZURE SCORE MONITORING TO EVALUATE THE ANTIEPILEPTOGENIC EFFECT OF SARCOSINE. WE USED IMMUNOHISTOCHEMISTRY AND WESTERN BLOT ANALYSIS FOR THE EVALUATION OF GLYT1 EXPRESSION AND EPIGENETIC CHANGES OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) IN THE EPILEPTOGENIC HIPPOCAMPI OF RATS, AND FURTHER EVALUATED EXPRESSION CHANGES IN ENZYMES INVOLVED IN THE REGULATION OF DNA METHYLATION, TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), DNA-METHYLTRANSFERASE 1 (DNMT1), AND DNMT3A. OUR RESULTS DEMONSTRATED: (I) EXPERIMENTAL EVIDENCE THAT SARCOSINE (3 G/KG, I.P. DAILY) SUPPRESSED KINDLING EPILEPTOGENESIS IN RATS; (II) THE SARCOSINE-INDUCED ANTIEPILEPTOGENIC EFFECT WAS ACCOMPANIED BY A SUPPRESSED HIPPOCAMPAL GLYT1 EXPRESSION AS WELL AS A REDUCTION OF HIPPOCAMPAL 5MC LEVELS AND A CORRESPONDING INCREASE IN 5HMC; AND (III) SARCOSINE TREATMENT CAUSED DIFFERENTIAL EXPRESSION CHANGES OF TET1 AND DNMTS. TOGETHER, THESE FINDINGS SUGGEST THAT SARCOSINE HAS UNPRECEDENTED DISEASE-MODIFYING PROPERTIES IN A KINDLING MODEL OF EPILEPTOGENESIS IN RATS, WHICH WAS ASSOCIATED WITH ALTERED HIPPOCAMPAL DNA METHYLATION. THUS, MANIPULATION OF THE GLYCINE SYSTEM IS A POTENTIAL THERAPEUTIC APPROACH TO ATTENUATE THE DEVELOPMENT OF EPILEPSY. 2020 14 5063 16 PHOSPHORYLATED HISTONE 3 AT SERINE 10 IDENTIFIES ACTIVATED SPINAL NEURONS AND CONTRIBUTES TO THE DEVELOPMENT OF TISSUE INJURY-ASSOCIATED PAIN. TRANSCRIPTIONAL CHANGES IN SUPERFICIAL SPINAL DORSAL HORN NEURONS (SSDHN) ARE ESSENTIAL IN THE DEVELOPMENT AND MAINTENANCE OF PROLONGED PAIN. EPIGENETIC MECHANISMS INCLUDING POST-TRANSLATIONAL MODIFICATIONS IN HISTONES ARE PIVOTAL IN REGULATING TRANSCRIPTION. HERE, WE REPORT THAT PHOSPHORYLATION OF SERINE 10 (S10) IN HISTONE 3 (H3) SPECIFICALLY OCCURS IN A GROUP OF RAT SSDHN FOLLOWING THE ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NEURONS BY BURN INJURY, CAPSAICIN APPLICATION OR SUSTAINED ELECTRICAL ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NERVE FIBRES. IN CONTRAST, BRIEF THERMAL OR MECHANICAL NOCICEPTIVE STIMULI, WHICH FAIL TO INDUCE TISSUE INJURY OR INFLAMMATION, DO NOT PRODUCE THE SAME EFFECT. BLOCKING N-METHYL-D-ASPARTATE RECEPTORS OR ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2, OR BLOCKING OR DELETING THE MITOGEN- AND STRESS-ACTIVATED KINASES 1 AND 2 (MSK1/2), WHICH PHOSPHORYLATE S10 IN H3, INHIBIT UP-REGULATION IN PHOSPHORYLATED S10 IN H3 (P-S10H3) AS WELL AS FOS TRANSCRIPTION, A DOWN-STREAM EFFECT OF P-S10H3. DELETING MSK1/2 ALSO INHIBITS THE DEVELOPMENT OF CARRAGEENAN-INDUCED INFLAMMATORY HEAT HYPERALGESIA IN MICE. WE PROPOSE THAT P-S10H3 IS A NOVEL MARKER FOR NOCICEPTIVE PROCESSING IN SSDHN WITH HIGH RELEVANCE TO TRANSCRIPTIONAL CHANGES AND THE DEVELOPMENT OF PROLONGED PAIN. 2017 15 1693 30 DUSP4 DEFICIENCY CAUSED BY PROMOTER HYPERMETHYLATION DRIVES JNK SIGNALING AND TUMOR CELL SURVIVAL IN DIFFUSE LARGE B CELL LYMPHOMA. THE EPIGENETIC DYSREGULATION OF TUMOR SUPPRESSOR GENES IS AN IMPORTANT DRIVER OF HUMAN CARCINOGENESIS. WE HAVE COMBINED GENOME-WIDE DNA METHYLATION ANALYSES AND GENE EXPRESSION PROFILING AFTER PHARMACOLOGICAL DNA DEMETHYLATION WITH FUNCTIONAL SCREENING TO IDENTIFY NOVEL TUMOR SUPPRESSORS IN DIFFUSE LARGE B CELL LYMPHOMA (DLBCL). WE FIND THAT A CPG ISLAND IN THE PROMOTER OF THE DUAL-SPECIFICITY PHOSPHATASE DUSP4 IS ABERRANTLY METHYLATED IN NODAL AND EXTRANODAL DLBCL, IRRESPECTIVE OF ABC OR GCB SUBTYPE, RESULTING IN LOSS OF DUSP4 EXPRESSION IN 75% OF >200 EXAMINED CASES. THE DUSP4 GENOMIC LOCUS IS FURTHER DELETED IN UP TO 13% OF AGGRESSIVE B CELL LYMPHOMAS, AND THE LACK OF DUSP4 IS A NEGATIVE PROGNOSTIC FACTOR IN THREE INDEPENDENT COHORTS OF DLBCL PATIENTS. ECTOPIC EXPRESSION OF WILD-TYPE DUSP4, BUT NOT OF A PHOSPHATASE-DEFICIENT MUTANT, DEPHOSPHORYLATES C-JUN N-TERMINAL KINASE (JNK) AND INDUCES APOPTOSIS IN DLBCL CELLS. PHARMACOLOGICAL OR DOMINANT-NEGATIVE JNK INHIBITION RESTRICTS DLBCL SURVIVAL IN VITRO AND IN VIVO AND SYNERGIZES STRONGLY WITH THE BRUTON'S TYROSINE KINASE INHIBITOR IBRUTINIB. OUR RESULTS INDICATE THAT DLBCL CELLS DEPEND ON JNK SIGNALING FOR SURVIVAL. THIS FINDING PROVIDES A MECHANISTIC BASIS FOR THE CLINICAL DEVELOPMENT OF JNK INHIBITORS IN DLBCL, IDEALLY IN SYNTHETIC LETHAL COMBINATIONS WITH INHIBITORS OF CHRONIC ACTIVE B CELL RECEPTOR SIGNALING. 2015 16 4696 22 NF-KAPPAB REPRESSES RETINOIC ACID RECEPTOR-MEDIATED GPRC5A TRANSACTIVATION IN LUNG EPITHELIAL CELLS TO PROMOTE NEOPLASIA. CHRONIC INFLAMMATION IS ASSOCIATED WITH LUNG TUMORIGENESIS, IN WHICH NF-KAPPAB-MEDIATED EPIGENETIC REGULATION PLAYS A CRITICAL ROLE. LUNG TUMOR SUPPRESSOR G PROTEIN-COUPLED RECEPTOR, FAMILY C, MEMBER 5A (GPRC5A), IS REPRESSED IN MOST NON-SMALL CELL LUNG CANCER (NSCLC); HOWEVER, THE MECHANISMS REMAIN UNCLEAR. HERE, WE SHOW THAT NF-KAPPAB ACTS AS A TRANSCRIPTIONAL REPRESSOR IN SUPPRESSION OF GPRC5A. NF-KAPPAB INDUCED GPRC5A REPRESSION BOTH IN VITRO AND IN VIVO. INTRIGUINGLY, TRANSACTIVATION OF NF-KAPPAB DOWNSTREAM TARGETS WAS NOT REQUIRED, BUT THE TRANSACTIVATION DOMAIN OF RELA/P65 WAS REQUIRED FOR GPRC5A REPRESSION. NF-KAPPAB DID NOT BIND TO ANY POTENTIAL CIS-ELEMENT IN THE GPRC5A PROMOTER. INSTEAD, P65 WAS COMPLEXED WITH RETINOIC ACID RECEPTOR ALPHA/BETA (RARALPHA/BETA) AND RECRUITED TO THE RA RESPONSE ELEMENT SITE AT THE GPRC5A PROMOTER, RESULTING IN DISRUPTED RNA POLYMERASE II COMPLEXING AND SUPPRESSED TRANSCRIPTION. NOTABLY, PHOSPHORYLATION ON SERINE 276 OF P65 WAS REQUIRED FOR INTERACTION WITH RARALPHA/BETA AND REPRESSION OF GPRC5A. MOREOVER, NF-KAPPAB-MEDIATED EPIGENETIC REPRESSION WAS THROUGH SUPPRESSION OF ACETYLATED HISTONE H3K9 (H3K9AC), BUT NOT DNA METHYLATION OF THE CPG ISLANDS, AT THE GPRC5A PROMOTER. CONSISTENTLY, A HISTONE DEACETYLASE INHIBITOR, BUT NOT DNA METHYLATION INHIBITOR, RESTORED GPRC5A EXPRESSION IN NSCLC CELLS. THUS, NF-KAPPAB INDUCES TRANSCRIPTIONAL REPRESSION OF GPRC5A VIA A COMPLEX WITH RARALPHA/BETA AND MEDIATES EPIGENETIC REPRESSION VIA SUPPRESSION OF H3K9AC. 2023 17 1455 26 DISCOVERY OF THIENO[2,3-D]PYRIMIDINE-BASED HYDROXAMIC ACID DERIVATIVES AS BROMODOMAIN-CONTAINING PROTEIN 4/HISTONE DEACETYLASE DUAL INHIBITORS INDUCE AUTOPHAGIC CELL DEATH IN COLORECTAL CARCINOMA CELLS. BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) AND HISTONE DEACETYLASES (HDAC) ARE BOTH ATTRACTIVE EPIGENETIC TARGETS IN CANCER AND OTHER CHRONIC DISEASES. BASED ON THE INTEGRATED FRAGMENT-BASED DRUG DESIGN, SYNTHESIS, AND IN VITRO AND IN VIVO EVALUATIONS, A SERIES OF NOVEL THIENO[2,3-D]PYRIMIDINE-BASED HYDROXAMIC ACID DERIVATIVES ARE DISCOVERED AS SELECTIVE BRD4-HDAC DUAL INHIBITORS. COMPOUND 17C IS THE MOST POTENT INHIBITOR FOR BRD4 AND HDAC WITH IC(50) VALUES AT NANOMOLAR LEVELS, AS WELL AS THE EXPRESSION LEVEL OF C-MYC, AND INCREASES THE ACETYLATION OF HISTONE H3. MOREOVER, 17C PRESENTS INHIBITORY EFFECTS ON THE PROLIFERATION OF COLORECTAL CARCINOMA (CRC) CELLS VIA INDUCING AUTOPHAGIC CELL DEATH. IT ALSO HAS A GOOD PHARMACOKINETIC PROFILE IN RATS AND ORAL BIOAVAILABILITY OF 40.5%. IN THE HCT-116 XENOGRAFT IN VIVO MODELS, 17C DISPLAYS POTENT INHIBITORY EFFICIENCY ON TUMOR GROWTH BY INDUCING AUTOPHAGIC CELL DEATH AND SUPPRESSING IL6-JAK-STAT SIGNALING PATHWAYS. OUR RESULTS SUGGEST THAT THE BRD4-HDAC DUAL INHIBITION MIGHT BE AN ATTRACTIVE THERAPEUTIC STRATEGY FOR CRC. 2020 18 6256 22 THE MITOGEN AND STRESS-ACTIVATED PROTEIN KINASE 1 REGULATES THE RAPID EPIGENETIC TAGGING OF DORSAL HORN NEURONS AND NOCIFENSIVE BEHAVIOUR. PHOSPHORYLATION OF HISTONE H3 AT SERINE 10 (P-H3S10) IS A MARKER OF ACTIVE GENE TRANSCRIPTION. USING COGNITIVE MODELS OF NEURAL PLASTICITY, P-H3S10 WAS SHOWN TO BE DOWNSTREAM OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALLING IN THE HIPPOCAMPUS. IN THIS STUDY, WE SHOW THAT NOCICEPTIVE SIGNALLING AFTER PERIPHERAL FORMALIN INJECTION INCREASED P-H3S10 EXPRESSION IN THE IPSILATERAL DORSAL HORN. THIS INCREASE WAS MAXIMAL 30 MINUTES AFTER FORMALIN INJECTION AND OCCURRED MAINLY WITHIN P-ERK-POSITIVE NEURONS. SPINAL P-H3S10-ENHANCED EXPRESSION WAS ALSO OBSERVED IN NEUROKININ 1 RECEPTOR (NK1R), C-FOS, AND ZIF268 POSITIVE NEURONS AND WAS INHIBITED BY ABLATION OF SEROTONERGIC DESCENDING CONTROLS. THE MITOGEN AND STRESS-ACTIVATED PROTEIN KINASE 1 (MSK1) IS DOWNSTREAM OF ERK AND CAN INDUCE P-H3S10. WE FOUND THAT, AFTER FORMALIN INJECTION, MOST PHOSPHO-MSK1 (P-MSK1)-POSITIVE CELLS (87% +/- 3%) EXPRESSED P-ERK AND THE MAJORITY OF P-H3S10-POSITIVE CELLS (85% +/- 5%) EXPRESSED P-MSK1. INHIBITION OF ERK ACTIVITY WITH THE MEK INHIBITOR SL327 REDUCED FORMALIN-INDUCED P-ERK, P-MSK1, AND P-H3S10, DEMONSTRATING THAT SPINAL P-MSK1 AND P-H3S10 WERE AT LEAST PARTLY DOWNSTREAM OF ERK SIGNALLING. CRUCIALLY, PHARMACOLOGICAL BLOCKADE OF SPINAL MSK1 ACTIVITY WITH THE NOVEL MSK1 INHIBITOR SB727651A INHIBITED FORMALIN-INDUCED SPINAL P-H3S10 AND NOCIFENSIVE BEHAVIOUR. THESE FINDINGS ARE THE FIRST TO ESTABLISH THE INVOLVEMENT OF P-H3S10 AND ITS MAIN KINASE, MSK1, IN ERK REGULATION OF NOCICEPTION. GIVEN THE GENERAL IMPORTANCE OF ERK SIGNALLING IN PAIN PROCESSING, OUR RESULTS SUGGEST THAT P-H3S10 COULD PLAY A ROLE IN THE RESPONSE TO INJURY. 2016 19 2379 27 EPIGENETIC REGULATION OF WNT PATHWAY ANTAGONISTS IN HUMAN GLIOBLASTOMA MULTIFORME. EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IS COMMON IN HUMAN CANCER. USING A LARGE-SCALE WHOLE-GENOME APPROACH IN AN EARLIER STUDY, THE AUTHORS IDENTIFIED EPIGENETICALLY SILENCED GENES WITH POTENTIAL TUMOR SUPPRESSOR FUNCTION IN GLIOBLASTOMA (GBM). THREE GENES IDENTIFIED IN THIS ANALYSIS-DKK1, SFRP1, AND WIF1-ARE POTENT INHIBITORS OF THE WNT SIGNAL TRANSDUCTION PATHWAY. HERE, THE AUTHORS CONFIRM DECREASED EXPRESSION OF THESE GENES IN GBM TUMOR TISSUE SAMPLES RELATIVE TO NONTUMOR BRAIN TISSUE SAMPLES USING REAL-TIME PCR. THEY THEN SHOW THAT EXPRESSION OF ALL 3 GENES IS RESTORED IN T98 GBM CELLS BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA), BUT ONLY DKK1 EXPRESSION IS RESTORED BY TREATMENT WITH THE DEMETHYLATING AGENT 5-AZACYTIDINE. BISULFITE SEQUENCING DID NOT REVEAL SIGNIFICANT METHYLATION IN THE PROMOTER REGION OF DKK1, WHEREAS HISTONE ACETYLATION AND CHROMATIN ACCESSIBILITY INCREASED SIGNIFICANTLY FOR ALL 3 GENES AFTER TSA TREATMENT. ECTOPIC EXPRESSION OF DKK1 SIGNIFICANTLY REDUCES COLONY FORMATION AND INCREASES CHEMOTHERAPY-INDUCED APOPTOSIS IN T98 CELLS. ECTOPIC EXPRESSION OF THE CANONICAL WNT PATHWAY INHIBITORS WIF1 AND SFRP1 SHOWS A RELATIVE LACK OF RESPONSE. CHRONIC WNT3A STIMULATION ONLY PARTIALLY REVERSES GROWTH SUPPRESSION AFTER DKK1 REEXPRESSION, WHEREAS A SPECIFIC INHIBITOR OF THE JNK PATHWAY SIGNIFICANTLY REVERSES THE EFFECT OF DKK1 REEXPRESSION ON COLONY FORMATION AND APOPTOSIS IN T98 CELLS. THESE RESULTS SUPPORT A POTENTIAL GROWTH-SUPPRESSIVE FUNCTION FOR EPIGENETICALLY SILENCED DKK1 IN GBM AND SUGGEST THAT DKK1 RESTORATION COULD MODULATE WNT SIGNALING THROUGH BOTH CANONICAL AND NONCANONICAL PATHWAYS. 2010 20 1783 23 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING. 2017