1 1141 119 CONCERTED CELL AND IN VIVO SCREEN FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDA) CHEMOTHERAPEUTICS. PDA IS A MAJOR CAUSE OF US CANCER-RELATED DEATHS. ONCOGENIC KRAS PRESENTS IN 90% OF HUMAN PDAS. KRAS MUTATIONS OCCUR EARLY IN PRE-NEOPLASTIC LESIONS BUT ARE INSUFFICIENT TO CAUSE PDA. OTHER CONTRIBUTING FACTORS EARLY IN DISEASE PROGRESSION INCLUDE CHRONIC PANCREATITIS, ALTERATIONS IN EPIGENETIC REGULATORS, AND TUMOR SUPPRESSOR GENE MUTATION. GPCRS ACTIVATE HETEROTRIMERIC G-PROTEINS THAT STIMULATE INTRACELLULAR CALCIUM AND ONCOGENIC KRAS SIGNALING, THEREBY PROMOTING PANCREATITIS AND PROGRESSION TO PDA. BY CONTRAST, RGS PROTEINS INHIBIT GI/Q-COUPLED GPCRS TO NEGATIVELY REGULATE PDA PROGRESSION. RGS16::GFP IS EXPRESSED IN RESPONSE TO CAERULEIN-INDUCED ACINAR CELL DEDIFFERENTIATION, EARLY NEOPLASIA, AND THROUGHOUT PDA PROGRESSION. IN GENETICALLY ENGINEERED MOUSE MODELS OF PDA, RGS16::GFP IS USEFUL FOR PRE-CLINICAL RAPID IN VIVO VALIDATION OF NOVEL CHEMOTHERAPEUTICS TARGETING EARLY LESIONS IN PATIENTS FOLLOWING SUCCESSFUL RESECTION OR AT HIGH RISK FOR PROGRESSING TO PDA. CULTURED PRIMARY PDA CELLS EXPRESS RGS16::GFP IN RESPONSE TO CYTOTOXIC DRUGS. A HISTONE DEACETYLASE INHIBITOR, TSA, STIMULATED RGS16::GFP EXPRESSION IN PDA PRIMARY CELLS, POTENTIATED GEMCITABINE AND JQ1 CYTOTOXICITY IN CELL CULTURE, AND GEM + TSA + JQ1 INHIBITED TUMOR INITIATION AND PROGRESSION IN VIVO. HERE WE ESTABLISH THE USE OF RGS16::GFP EXPRESSION FOR TESTING DRUG COMBINATIONS IN CELL CULTURE AND VALIDATION OF BEST CANDIDATES IN OUR RAPID IN VIVO SCREEN. 2020 2 3195 37 HDAC INHIBITORS AUGMENTED CELL MIGRATION AND METASTASIS THROUGH INDUCTION OF PKCS LEADING TO IDENTIFICATION OF LOW TOXICITY MODALITIES FOR COMBINATION CANCER THERAPY. PURPOSE: HISTONE DEACETYLASE INHIBITORS (HDACI) ARE ACTIVELY EXPLORED AS NEW-GENERATION EPIGENETIC DRUGS BUT HAVE LOW EFFICACY IN CANCER MONOTHERAPY. TO REVEAL NEW MECHANISM FOR COMBINATION THERAPY, WE SHOW THAT HDACI INDUCE CELL DEATH BUT SIMULTANEOUSLY ACTIVATE TUMOR-PROGRESSIVE GENES TO RUIN THERAPEUTIC EFFICACY. COMBINED TREATMENTS TO TARGET TUMORIGENESIS AND HDACI-ACTIVATED METASTASIS WITH LOW TOXIC MODALITIES COULD DEVELOP NEW STRATEGIES FOR LONG-TERM CANCER THERAPY. EXPERIMENTAL DESIGN: BECAUSE METASTASIS IS THE MAJOR CAUSE OF CANCER MORTALITY, WE MEASURED CELL MIGRATION ACTIVITY AND PROFILED METASTASIS-RELATED GENE EXPRESSIONS IN HDACI-TREATED CANCER CELLS. WE DEVELOPED LOW TOXIC COMBINATION MODALITIES TARGETING TUMORIGENESIS AND HDACI-ACTIVATED METASTASIS FOR PRECLINICAL THERAPIES IN MICE. RESULTS: WE SHOWED THAT CELL MIGRATION ACTIVITY WAS DRAMATICALLY AND DOSE DEPENDENTLY ENHANCED BY VARIOUS CLASSES OF HDACI TREATMENTS IN 13 OF 30 EXAMINED HUMAN BREAST, GASTRIC, LIVER, AND LUNG CANCER CELL LINES. TUMOR METASTASIS WAS ALSO ENHANCED IN HDACI-TREATED MICE. HDACI TREATMENTS ACTIVATED MULTIPLE PKCS AND DOWNSTREAM SUBSTRATES ALONG WITH UPREGULATED PROAPOPTOTIC P21. FOR TARGETING TUMORIGENESIS AND METASTASIS WITH IMMEDIATE CLINICAL IMPACT, WE SHOWED THAT NEW MODALITIES OF HDACI COMBINED DRUGS WITH PKC INHIBITORY AGENT, CURCUMIN OR TAMOXIFEN, NOT ONLY SUPPRESSED HDACI-ACTIVATED TUMOR PROGRESSIVE PROTEINS AND CELL MIGRATION IN VITRO BUT ALSO INHIBITED TUMOR GROWTH AND METASTASIS IN VIVO. CONCLUSION: TREATMENTS OF DIFFERENT STRUCTURAL CLASSES OF HDACI SIMULTANEOUSLY INDUCED CELL DEATH AND PROMOTED CELL MIGRATION AND METASTASIS IN MULTIPLE CANCER CELL TYPES. SUPPRESSION OF HDACI-INDUCED PKCS LEADS TO DEVELOPMENT OF LOW TOXIC AND LONG-TERM THERAPEUTIC STRATEGIES TO POTENTIALLY TREAT CANCER AS A CHRONIC DISEASE. 2012 3 402 25 ANALYSIS OF APOPTOSOME DYSREGULATION IN PANCREATIC CANCER AND OF ITS ROLE IN CHEMORESISTANCE. THE APOPTOSOME IS A MULTIPROTEIN COMPLEX MEDIATING THE MITOCHONDRIAL PATHWAY OF CELL DEATH. ITS IMPORTANCE DURING DEVELOPMENT HAS BEEN CLEARLY DEMONSTRATED BY KNOCKING OUT KEY GENES IN MOUSE. APAF1 IS THE CORE PROTEIN OF THE APOPTOSOME AND ITS DOSAGE IS ALSO CRITICAL IN VARIOUS CANCER TYPES, I.E., MELANOMA, GERM LINE TUMOR, GASTROINTESTINAL CANCER AND B-TYPE CHRONIC LYMPHOCYTIC LEUKEMIA. THIS IS GENERALLY DUE TO INACTIVATION OF THE APAF1 LOCUS BY EPIGENETIC PHENOMENA OR BY ACTIVITY OF PROMOTER REGULATORS. WE INVESTIGATED THE PUTATIVE ROLES OF THE APOPTOSOME IN PANCREATIC DUCTAL ADENOCARCINOMA (PDAC). WE FOUND THAT BOTH APAF1 MRNA AND PROTEIN ARE DYSREGULATED IN HUMAN PDAC SAMPLES. SIMILARLY, SEVERAL PDAC CELL LINES EXHIBITED VARIABLE LEVELS OF BOTH APAF1 PROTEIN AND MRNA. THE RESPONSE TO CELL DEATH INDUCTION AND ITS BIOCHEMICAL FEATURES WERE ASSESSED BY TREATMENT OF EACH LINE WITH COMMONLY USED CHEMOTHERAPEUTIC AGENTS. WE FOUND THAT THE APOPTOSOME PATHWAY WAS NOT FUNCTIONAL IN MOST CELL LINES UPON CYTOCHROME C RELEASE FROM MITOCHONDRIA. IN ADDITION, WE RESTORED APAF1 AND CASPASE-9 DOSAGE IN PANC-1 CELLS, WHERE THE APOPTOSOME IS DOWNREGULATED, BY OVEREXPRESSING THE MURINE CDNA OF THE TWO MOLECULES, AND WE IMPROVED THE DEATH RESPONSE TO CHEMOTHERAPEUTIC AGENTS. 2007 4 1902 25 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 5 5688 28 SILENCING EFFECTS OF MUTANT RAS SIGNALLING ON TRANSCRIPTOMES. MUTATED GENES OF THE RAS FAMILY ENCODING SMALL GTP-BINDING PROTEINS DRIVE NUMEROUS CANCERS, INCLUDING PANCREATIC, COLON AND LUNG TUMORS. BESIDES THE NUMEROUS EFFECTS OF MUTANT RAS GENE EXPRESSION ON ABERRANT PROLIFERATION, TRANSFORMED PHENOTYPES, METABOLISM, AND THERAPY RESISTANCE, THE MOST STRIKING CONSEQUENCES OF CHRONIC RAS ACTIVATION ARE CHANGES OF THE GENETIC PROGRAM. BY PERFORMING SYSTEMATIC GENE EXPRESSION STUDIES IN CELLULAR MODELS THAT ALLOW COMPARISONS OF PRE-NEOPLASTIC WITH RAS-TRANSFORMED CELLS, WE AND OTHERS HAVE ESTIMATED THAT 7 PERCENT OR MORE OF ALL TRANSCRIPTS ARE ALTERED IN CONJUNCTION WITH THE EXPRESSION OF THE ONCOGENE. IN THIS CONTEXT, THE NUMBER OF UP-REGULATED TRANSCRIPTS APPROXIMATES THAT OF DOWN-REGULATED TRANSCRIPTS. WHILE UP-REGULATED TRANSCRIPTION FACTORS SUCH AS MYC, FOSL1, AND HMGA2 HAVE BEEN IDENTIFIED AND CHARACTERIZED AS RAS-RESPONSIVE DRIVERS OF THE ALTERED TRANSCRIPTOME, THE SUPPRESSED FACTORS HAVE BEEN LESS WELL STUDIED AS POTENTIAL REGULATORS OF THE GENETIC PROGRAM AND TRANSFORMED PHENOTYPE IN THE BREADTH OF THEIR OCCURRENCE. WE THEREFORE HAVE COLLECTED INFORMATION ON DOWNREGULATED RAS-RESPONSIVE FACTORS AND DISCUSS THEIR POTENTIAL ROLE AS TUMOR SUPPRESSORS THAT ARE LIKELY TO ANTAGONIZE ACTIVE CANCER DRIVERS. TO BETTER UNDERSTAND THE ACTIVE MECHANISMS THAT ENTAIL ANTI-RAS FUNCTION AND THOSE THAT LEAD TO LOSS OF TUMOR SUPPRESSOR ACTIVITY, WE FOCUS ON THE TUMOR SUPPRESSOR HREV107 (ALIAS PLAAT3 [PHOSPHOLIPASE A AND ACYLTRANSFERASE 3], PLA2G16 [PHOSPHOLIPASE A2, GROUP XVI] AND HRASLS3 [HRAS-LIKE SUPPRESSOR 3]). INACTIVATING HREV107 MUTATIONS IN TUMORS ARE EXTREMELY RARE, HENCE EPIGENETIC CAUSES MODULATED BY THE RAS PATHWAY ARE LIKELY TO LEAD TO DOWN-REGULATION AND LOSS OF FUNCTION. 2023 6 194 23 ACETYLSHIKONIN SUPPRESSES INVASION OF PORPHYROMONAS GINGIVALIS?INFECTED YD10B ORAL CANCER CELLS BY MODULATING THE INTERLEUKIN-8/MATRIX METALLOPROTEINASE AXIS. THE DEVELOPMENT OF PHARMACEUTICAL AGENTS POSSESSING ANTI?INVASIVE AND ANTI?METASTATIC ABILITIES, AS WELL AS APOPTOTIC ACTIVITY, IS IMPORTANT IN DECREASING THE INCIDENCE AND RECURRENCE OF ORAL CANCER. CANCER CELLS ARE KNOWN TO ACQUIRE INVASIVENESS NOT ONLY THROUGH EPIGENETIC CHANGES, BUT ALSO FROM INFLAMMATORY STIMULI WITHIN THE TUMOR MICROENVIRONMENT. ACCORDINGLY, THE IDENTIFICATION OF AGENTS THAT CAN SUPPRESS THE INFLAMMATION?PROMOTED INVASIVENESS OF CANCER CELLS MAY BE IMPORTANT IN TREATING CANCER AND IMPROVING THE PROGNOSIS OF PATIENTS WITH CANCER. ACETYLSHIKONIN, A FLAVONOID WITH ANTI?INFLAMMATORY ACTIVITY, INHIBITS PROLIFERATION AND INDUCES APOPTOSIS OF ORAL CANCER CELLS. IN THE PRESENT STUDY, THE ANTI?INVASIVE EFFECT OF ACETYLSHIKONIN ON YD10B ORAL CANCER CELLS INFECTED WITH PORPHYROMONAS GINGIVALIS, A MAJOR PATHOGEN OF CHRONIC PERIODONTITIS, AND THE MECHANISMS INVOLVED WERE INVESTIGATED. FIRSTLY, WE EXAMINED WHETHER P. GINGIVALIS INFECTION INCREASED THE INVASIVENESS OF YD10B CELLS. RESULTS SUGGESTED THAT YD10B ORAL CANCER CELLS BECOME MORE AGGRESSIVE WHEN THEY ARE INFECTED WITH P. GINGIVALIS. SECONDLY, ACETYLSHIKONIN SIGNIFICANTLY INHIBITED THE INVASION OF P. GINGIVALIS?INFECTED YD10B CELLS BY SUPPRESSING IL?8 RELEASE AND IL?8?DEPENDENT MMP RELEASE. THESE DATA SUGGEST THAT ACETYLSHIKONIN MAY BE A USEFUL PREVENTIVE AND THERAPEUTIC CANDIDATE FOR ORAL CANCER THAT IS CHRONICALLY INFECTED WITH PERIODONTAL PATHOGENS. 2018 7 1966 29 EPIGENETIC ALTERATION OF PRKCDBP IN COLORECTAL CANCERS AND ITS IMPLICATION IN TUMOR CELL RESISTANCE TO TNFALPHA-INDUCED APOPTOSIS. PURPOSE: PRKCDBP IS A PUTATIVE TUMOR SUPPRESSOR IN WHICH ALTERATION HAS BEEN OBSERVED IN SEVERAL HUMAN CANCERS. WE INVESTIGATED EXPRESSION AND FUNCTION OF PRKCDBP IN COLORECTAL CELLS AND TISSUES TO EXPLORE ITS CANDIDACY AS A SUPPRESSOR IN COLORECTAL TUMORIGENESIS. EXPERIMENTAL DESIGN: EXPRESSION AND METHYLATION STATUS OF PRKCDBP AND ITS EFFECT ON TUMOR GROWTH WERE EVALUATED. TRANSCRIPTIONAL REGULATION BY NF-KAPPAB SIGNALING WAS DEFINED BY LUCIFERASE REPORTER AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: PRKCDBP EXPRESSION WAS HARDLY DETECTABLE IN 29 OF 80 (36%) PRIMARY TUMORS AND 11 OF 19 (58%) CELL LINES, AND ITS ALTERATION CORRELATED WITH TUMOR STAGE AND GRADE. PROMOTER HYPERMETHYLATION WAS COMMONLY FOUND IN CANCERS. PRKCDBP EXPRESSION INDUCED THE G(1) CELL-CYCLE ARREST AND INCREASED CELLULAR SENSITIVITY TO VARIOUS APOPTOTIC STRESSES. PRKCDBP WAS INDUCED BY TNFALPHA, AND ITS LEVEL CORRELATED WITH TUMOR CELL SENSITIVITY TO TNFALPHA-INDUCED APOPTOSIS. PRKCDBP INDUCTION BY TNFALPHA WAS DISRUPTED BY BLOCKING NF-KAPPAB SIGNALING WHILE IT WAS ENHANCED BY RELA TRANSFECTION. THE PRKCDBP PROMOTER ACTIVITY WAS INCREASED IN RESPONSE TO TNFALPHA, AND THIS RESPONSE WAS ABOLISHED BY DISRUPTION OF A KAPPAB SITE IN THE PROMOTER. PRKCDBP DELAYED THE FORMATION AND GROWTH OF XENOGRAFT TUMORS AND IMPROVED TUMOR RESPONSE TO TNFALPHA-INDUCED APOPTOSIS. CONCLUSIONS: PRKCDBP IS A PROAPOPTOTIC TUMOR SUPPRESSOR WHICH IS COMMONLY ALTERED IN COLORECTAL CANCER BY PROMOTER HYPERMETHYLATION, AND ITS GENE TRANSCRIPTION IS DIRECTLY ACTIVATED BY NF-KAPPAB IN RESPONSE TO TNFALPHA. THIS SUGGESTS THAT PRKCDBP INACTIVATION MAY CONTRIBUTE TO TUMOR PROGRESSION BY REDUCING CELLULAR SENSITIVITY TO TNFALPHA AND OTHER STRESSES, PARTICULARLY UNDER CHRONIC INFLAMMATORY MICROENVIRONMENT. 2011 8 5491 30 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 9 6421 29 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES. 2018 10 6132 38 THE EPIGENETIC REGULATORS BMI1 AND RING1B ARE DIFFERENTIALLY REGULATED IN PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA. CHRONIC PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) ARE ASSOCIATED WITH MAJOR CHANGES IN CELL DIFFERENTIATION. THESE CHANGES MAY BE AT THE BASIS OF THE INCREASED RISK FOR PDAC AMONG PATIENTS WITH CHRONIC PANCREATITIS. POLYCOMB PROTEINS ARE EPIGENETIC SILENCERS EXPRESSED IN ADULT STEM CELLS; UP-REGULATION OF POLYCOMB PROTEINS HAS BEEN REPORTED TO OCCUR IN A VARIETY OF SOLID TUMOURS SUCH AS COLON AND BREAST CANCER. WE HYPOTHESIZED THAT POLYCOMB MIGHT PLAY A ROLE IN PRENEOPLASTIC STATES IN THE PANCREAS AND IN TUMOUR DEVELOPMENT/PROGRESSION. TO TEST THESE IDEAS, WE DETERMINED THE EXPRESSION OF PRC1 COMPLEX PROTEINS (BMI1 AND RING1B) DURING PANCREATIC DEVELOPMENT AND IN PANCREATIC TISSUE FROM MOUSE MODELS OF DISEASE: ACUTE AND CHRONIC PANCREATIC INJURY, DUCT LIGATION, AND IN K-RAS(G12V) CONDITIONAL KNOCK-IN AND CAERULEIN-TREATED K-RAS(G12V) MICE. THE STUDY WAS EXTENDED TO HUMAN PANCREATIC TISSUE SAMPLES. TO OBTAIN MECHANISTIC INSIGHTS, BMI1 EXPRESSION IN CELLS UNDERGOING IN VITRO EXOCRINE CELL METAPLASIA AND THE EFFECTS OF BMI1 DEPLETION IN AN ACINAR CANCER CELL LINE WERE STUDIED. WE FOUND THAT BMI1 AND RING1B ARE EXPRESSED IN PANCREATIC EXOCRINE PRECURSOR CELLS DURING EARLY DEVELOPMENT AND IN DUCTAL AND ISLET CELLS-BUT NOT ACINAR CELLS-IN THE ADULT PANCREAS. BMI1 EXPRESSION WAS INDUCED IN ACINAR CELLS DURING ACUTE INJURY, IN ACINAR-DUCTAL METAPLASTIC LESIONS, AS WELL AS IN PANCREATIC INTRAEPITHELIAL NEOPLASIA (PANIN) AND PDAC. IN CONTRAST, RING1B EXPRESSION WAS ONLY SIGNIFICANTLY AND PERSISTENTLY UP-REGULATED IN HIGH-GRADE PANINS AND IN PDAC. BMI1 KNOCKDOWN IN CULTURED ACINAR TUMOUR CELLS LED TO CHANGES IN THE EXPRESSION OF VARIOUS DIGESTIVE ENZYMES. OUR RESULTS SUGGEST THAT BMI1 AND RING1B ARE MODULATED IN PANCREATIC DISEASES AND COULD CONTRIBUTE DIFFERENTLY TO TUMOUR DEVELOPMENT. 2009 11 5785 24 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 12 2395 31 EPIGENETIC REPROGRAMMING IN MIST1(-/-) MICE PREDICTS THE MOLECULAR RESPONSE TO CERULEIN-INDUCED PANCREATITIS. GENE EXPRESSION IS AFFECTED BY MODIFICATIONS TO HISTONE CORE PROTEINS WITHIN CHROMATIN. CHANGES IN THESE MODIFICATIONS, OR EPIGENETIC REPROGRAMMING, CAN DICTATE CELL FATE AND PROMOTE SUSCEPTIBILITY TO DISEASE. THE GOAL OF THIS STUDY WAS TO DETERMINE THE EXTENT OF EPIGENETIC REPROGRAMMING IN RESPONSE TO CHRONIC STRESS THAT OCCURS FOLLOWING ABLATION OF MIST1 (MIST1(-/-) ), WHICH IS REPRESSED IN PANCREATIC DISEASE. CHROMATIN IMMUNOPRECIPITATION FOR TRIMETHYLATION OF LYSINE RESIDUE 4 ON HISTONE 3 (H3K4ME3) IN PURIFIED ACINAR CELLS FROM WILD TYPE AND MIST1(-/-) MICE WAS FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) OR CHIP-QPCR. H3K4ME3-ENRICHED GENES WERE ASSESSED FOR EXPRESSION BY QRT-PCR IN PANCREATIC TISSUE BEFORE AND AFTER INDUCTION OF CERULEIN-INDUCED PANCREATITIS. WHILE MOST OF H3K4ME3-ENRICHMENT IS RESTRICTED TO TRANSCRIPTIONAL START SITES, >25% OF ENRICHMENT SITES ARE FOUND WITHIN, DOWNSTREAM OR BETWEEN ANNOTATED GENES. LESS THAN 10% OF THESE SITES WERE ALTERED IN MIST1(-/-) ACINI, WITH MOST CHANGES IN H3K4ME3 ENRICHMENT NOT REFLECTING ALTERED GENE EXPRESSION. INGENUITY PATHWAY ANALYSIS OF GENES DIFFERENTIALLY-ENRICHED FOR H3K4ME3 REVEALED AN ASSOCIATION WITH PANCREATITIS AND PANCREATIC DUCTAL ADENOCARCINOMA IN MIST1(-/-) TISSUE. MOST OF THESE GENES WERE NOT DIFFERENTIALLY EXPRESSED BUT SEVERAL WERE READILY INDUCED BY ACUTE EXPERIMENTAL PANCREATITIS, WITH SIGNIFICANTLY INCREASED EXPRESSION IN MIST1(-/-) TISSUE RELATIVE TO WILD TYPE MICE. WE SUGGEST THAT THE CHRONIC CELL STRESS OBSERVED IN THE ABSENCE OF MIST1 RESULTS IN EPIGENETIC REPROGRAMMING OF GENES INVOLVED IN PROMOTING PANCREATITIS TO A POISED STATE, THEREBY INCREASING THE SENSITIVITY TO EVENTS THAT PROMOTE DISEASE. 2014 13 2388 24 EPIGENETIC REMODELLING LICENCES ADULT CHOLANGIOCYTES FOR ORGANOID FORMATION AND LIVER REGENERATION. FOLLOWING SEVERE OR CHRONIC LIVER INJURY, ADULT DUCTAL CELLS (CHOLANGIOCYTES) CONTRIBUTE TO REGENERATION BY RESTORING BOTH HEPATOCYTES AND CHOLANGIOCYTES. WE RECENTLY SHOWED THAT DUCTAL CELLS CLONALLY EXPAND AS SELF-RENEWING LIVER ORGANOIDS THAT RETAIN THEIR DIFFERENTIATION CAPACITY INTO BOTH HEPATOCYTES AND DUCTAL CELLS. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH ADULT DUCTAL-COMMITTED CELLS ACQUIRE CELLULAR PLASTICITY, INITIATE ORGANOIDS AND REGENERATE THE DAMAGED TISSUE REMAIN LARGELY UNKNOWN. HERE, WE DESCRIBE THAT DUCTAL CELLS UNDERGO A TRANSIENT, GENOME-WIDE, REMODELLING OF THEIR TRANSCRIPTOME AND EPIGENOME DURING ORGANOID INITIATION AND IN VIVO FOLLOWING TISSUE DAMAGE. TET1-MEDIATED HYDROXYMETHYLATION LICENCES DIFFERENTIATED DUCTAL CELLS TO INITIATE ORGANOIDS AND ACTIVATE THE REGENERATIVE PROGRAMME THROUGH THE TRANSCRIPTIONAL REGULATION OF STEM-CELL GENES AND REGENERATIVE PATHWAYS INCLUDING THE YAP-HIPPO SIGNALLING. OUR RESULTS ARGUE IN FAVOUR OF THE REMODELLING OF GENOMIC METHYLOME/HYDROXYMETHYLOME LANDSCAPES AS A GENERAL MECHANISM BY WHICH DIFFERENTIATED CELLS EXIT A COMMITTED STATE IN RESPONSE TO TISSUE DAMAGE. 2019 14 3660 30 INDUCTION OF HEPATIC DIFFERENTIATION OF MOUSE BONE MARROW STROMAL STEM CELLS BY THE HISTONE DEACETYLASE INHIBITOR VPA. BONE MARROW STROMAL STEM CELLS (BMSSCS) MAY HAVE POTENTIAL TO DIFFERENTIATE IN VITRO AND IN VIVO INTO HEPATOCYTES. HERE, WE INVESTIGATED THE EFFECTS OF VALPROIC ACID (VPA) INVOLVED IN EPIGENETIC MODIFICATION, A DIRECT INHIBITOR OF HISTONE DEACETYLASE, ON HEPATIC DIFFERENTIATION OF MOUSE BMSSCS. FOLLOWING THE TREATMENT OF 2.5 MM VPA FOR 72 HRS, THE IN VITRO EXPANDED, HIGHLY PURIFIED AND FUNCTIONALLY ACTIVE MOUSE BMSSCS FROM BONE MARROW WERE EITHER EXPOSED TO SOME WELL-DEFINED CYTOKINES AND GROWTH FACTORS IN A SEQUENTIAL WAY (FIBROBLAST GROWTH FACTOR-4 [FGF-4], FOLLOWED BY HGF, AND HGF + OSM + ITS + DEXAMETHASONE, RESEMBLING THE ORDER OF SECRETION DURING LIVER EMBRYOGENESIS) OR TRANSPLANTED (CAUDAL VEIN) IN MICE SUBMITTED TO A PROTOCOL OF CHRONIC INJURY (CHRONIC I.P. INJECTION OF CCL4). ADDITIONAL EXPOSURE OF THE CELLS TO VPA CONSIDERABLY IMPROVED THE IN VITRO DIFFERENTIATION, AS DEMONSTRATED BY A MORE HOMOGENEOUS CELL POPULATION EXHIBITED EPITHELIAL MORPHOLOGY, INCREASING EXPRESSION OF HEPATIC SPECIAL GENES AND ENHANCED HEPATIC FUNCTIONS. FURTHER MORE, IN VIVO RESULTS INDICATE THAT THE PRE-TREATMENT OF VPA SIGNIFICANTLY INCREASED THE HOMING EFFICIENCY OF BMSSCS TO THE SITE OF LIVER INJURY AND, ADDITIONALLY, FOR SUPPORTING HEPATIC DIFFERENTIATION AS WELL AS IN VITRO. WE HAVE DEMONSTRATED THE USEFULNESS OF VPA IN THE TRANSDIFFERENTIATION OF BMSSCS INTO HEPATOCYTES BOTH IN VITRO AND IN VIVO, AND REGULATION OF FIBROBLAST GROWTH FACTOR RECEPTORS (FGFRS) AND C-MET GENE EXPRESSION THROUGH POST-TRANSLATIONAL MODIFICATION OF CORE HISTONES MIGHT BE THE PRIMARY INITIATING EVENT FOR THESE EFFECTS. THIS MODE COULD BE HELPFUL FOR LIVER ENGINEERING AND CLINICAL THERAPY. 2009 15 4558 26 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 16 4414 22 MOLECULAR AND CELLULAR MECHANISMS OF PROPOLIS AND ITS POLYPHENOLIC COMPOUNDS AGAINST CANCER. IN RECENT YEARS, INTEREST IN NATURAL PRODUCTS SUCH AS ALTERNATIVE SOURCES OF PHARMACEUTICALS FOR NUMEROUS CHRONIC DISEASES, INCLUDING TUMORS, HAS BEEN RENEWED. PROPOLIS, A NATURAL PRODUCT COLLECTED BY HONEYBEES, AND POLYPHENOLIC/FLAVONOID PROPOLIS-RELATED COMPONENTS MODULATE ALL STEPS OF THE CANCER PROGRESSION PROCESS. ANTICANCER ACTIVITY OF PROPOLIS AND ITS COMPOUNDS RELIES ON VARIOUS MECHANISMS: CELL-CYCLE ARREST AND ATTENUATION OF CANCER CELLS PROLIFERATION, REDUCTION IN THE NUMBER OF CANCER STEM CELLS, INDUCTION OF APOPTOSIS, MODULATION OF ONCOGENE SIGNALING PATHWAYS, INHIBITION OF MATRIX METALLOPROTEINASES, PREVENTION OF METASTASIS, ANTI-ANGIOGENESIS, ANTI-INFLAMMATORY EFFECTS ACCOMPANIED BY THE MODULATION OF THE TUMOR MICROENVIRONMENT (BY MODIFYING MACROPHAGE ACTIVATION AND POLARIZATION), EPIGENETIC REGULATION, ANTIVIRAL AND BACTERICIDAL ACTIVITIES, MODULATION OF GUT MICROBIOTA, AND ATTENUATION OF CHEMOTHERAPY-INDUCED DELETERIOUS SIDE EFFECTS. INGREDIENTS FROM PROPOLIS ALSO "SENSITIZE" CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, LIKELY BY BLOCKING THE ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB). IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE RELATED TO THE THE EFFECTS OF FLAVONOIDS AND OTHER POLYPHENOLIC COMPOUNDS FROM PROPOLIS ON TUMOR GROWTH AND METASTASIZING ABILITY, AND DISCUSS POSSIBLE MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE MODULATION OF INFLAMMATORY PATHWAYS AND CELLULAR PROCESSES THAT AFFECT SURVIVAL, PROLIFERATION, INVASION, ANGIOGENESIS, AND METASTASIS OF THE TUMOR. 2022 17 6584 26 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 18 2340 34 EPIGENETIC REGULATION OF LEUKOCYTE INFLAMMATORY MEDIATOR PRODUCTION DICTATES STAPHYLOCOCCUS AUREUS CRANIOTOMY INFECTION OUTCOME. STAPHYLOCOCCUS AUREUS IS A COMMON CAUSE OF SURGICAL-SITE INFECTIONS, INCLUDING THOSE ARISING AFTER CRANIOTOMY, WHICH IS PERFORMED TO ACCESS THE BRAIN FOR THE TREATMENT OF TUMORS, EPILEPSY, OR HEMORRHAGE. CRANIOTOMY INFECTION IS CHARACTERIZED BY COMPLEX SPATIAL AND TEMPORAL DYNAMICS OF LEUKOCYTE RECRUITMENT AND MICROGLIAL ACTIVATION. WE RECENTLY IDENTIFIED UNIQUE TRANSCRIPTIONAL PROFILES OF THESE IMMUNE POPULATIONS DURING S. AUREUS CRANIOTOMY INFECTION. EPIGENETIC PROCESSES ALLOW RAPID AND REVERSIBLE CONTROL OVER GENE TRANSCRIPTION; HOWEVER, LITTLE IS KNOWN ABOUT HOW EPIGENETIC PATHWAYS INFLUENCE IMMUNITY TO LIVE S. AUREUS. AN EPIGENETIC COMPOUND LIBRARY SCREEN IDENTIFIED BROMODOMAIN AND EXTRATERMINAL DOMAIN-CONTAINING (BET) PROTEINS AND HISTONE DEACETYLASES (HDACS) AS CRITICAL FOR REGULATING TNF, IL-6, IL-10, AND CCL2 PRODUCTION BY PRIMARY MOUSE MICROGLIA, MACROPHAGES, NEUTROPHILS, AND GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN RESPONSE TO LIVE S. AUREUS. CLASS I HDACS (C1HDACS) WERE INCREASED IN THESE CELL TYPES IN VITRO AND IN VIVO DURING ACUTE DISEASE IN A MOUSE MODEL OF S. AUREUS CRANIOTOMY INFECTION. HOWEVER, SUBSTANTIAL REDUCTIONS IN C1HDACS WERE OBSERVED DURING CHRONIC INFECTION, HIGHLIGHTING TEMPORAL REGULATION AND THE IMPORTANCE OF THE TISSUE MICROENVIRONMENT FOR DICTATING C1HDAC EXPRESSION. MICROPARTICLE DELIVERY OF HDAC AND BET INHIBITORS IN VIVO CAUSED WIDESPREAD DECREASES IN INFLAMMATORY MEDIATOR PRODUCTION, WHICH SIGNIFICANTLY INCREASED BACTERIAL BURDEN IN THE BRAIN, GALEA, AND BONE FLAP. THESE FINDINGS IDENTIFY HISTONE ACETYLATION AS AN IMPORTANT MECHANISM FOR REGULATING CYTOKINE AND CHEMOKINE PRODUCTION ACROSS DIVERSE IMMUNE CELL LINEAGES THAT IS CRITICAL FOR BACTERIAL CONTAINMENT. ACCORDINGLY, ABERRANT EPIGENETIC REGULATION MAY BE IMPORTANT FOR PROMOTING S. AUREUS PERSISTENCE DURING CRANIOTOMY INFECTION. 2023 19 5088 27 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 20 1260 28 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021