1 2391 131 EPIGENETIC REPRESSION OF DNA MISMATCH REPAIR BY INFLAMMATION AND HYPOXIA IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED COLORECTAL CANCER. SPORADIC HUMAN MISMATCH REPAIR (MMR)-DEFICIENT COLORECTAL CANCERS ACCOUNT FOR APPROXIMATELY 12.5% OF ALL CASES OF COLORECTAL CANCER. MMR-DEFICIENT COLORECTAL CANCERS ARE CLASSICALLY CHARACTERIZED BY RIGHT-SIDED LOCATION, MULTIFOCALITY, MUCINOUS HISTOLOGY, AND LYMPHOCYTIC INFILTRATION. HOWEVER, TUMORS IN GERM-LINE MMR-DEFICIENT MOUSE MODELS LACK THESE HISTOPATHOLOGIC FEATURES. MICE LACKING THE HETEROTRIMERIC G PROTEIN ALPHA SUBUNIT GIALPHA2 DEVELOP CHRONIC COLITIS AND MULTIFOCAL, RIGHT-SIDED CANCERS WITH MUCINOUS HISTOPATHOLOGY, SIMILAR TO HUMAN MMR-DEFICIENT COLORECTAL CANCER. YOUNG GIALPHA2-/- COLONIC EPITHELIUM HAS NORMAL MMR EXPRESSION BUT SELECTIVELY LOSES MLH1 AND CONSEQUENTLY PMS2 EXPRESSION FOLLOWING INFLAMMATION. GIALPHA2-/- CANCERS HAVE MICROSATELLITE INSTABILITY. MLH1 IS EPIGENETICALLY SILENCED NOT BY PROMOTER HYPERMETHYLATION BUT BY DECREASED HISTONE ACETYLATION. CHRONICALLY INFLAMED GIALPHA2-/- COLONIC MUCOSA CONTAINS PATCHY HYPOXIA, WITH INCREASED CRYPT EXPRESSION OF THE HYPOXIA MARKERS DEC-1 AND BNIP3. CHROMATIN IMMUNOPRECIPITATION IDENTIFIED INCREASED BINDING OF THE TRANSCRIPTIONAL REPRESSOR DEC-1 TO THE PROXIMAL MLH1 PROMOTER IN HYPOXIC YAMC CELLS AND COLITIC GIALPHA2-/- CRYPTS. TREATING GIALPHA2-/- MICE WITH THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY DECREASED COLITIS ACTIVITY AND RESCUED MLH1 EXPRESSION IN CRYPT EPITHELIAL CELLS, WHICH WAS ASSOCIATED WITH INCREASED ACETYL HISTONE H3 LEVELS AND DECREASED DEC-1 BINDING AT THE PROXIMAL MLH1 PROMOTER, CONSISTENT WITH A HISTONE DEACETYLASE-DEPENDENT MECHANISM. THESE DATA LINK CHRONIC HYPOXIC INFLAMMATION, EPIGENETIC MMR PROTEIN DOWN-REGULATION, DEVELOPMENT OF MMR-DEFICIENT COLORECTAL CANCER, AND THE FIRSTMOUSE MODEL OF SOMATICALLY ACQUIRED MMR-DEFICIENT COLORECTAL CANCER.	2009	
                                                                                                                                                                                                                                                                                                                                                                                            
2 1966  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                     
3  714  25 CADMIUM IS A MUTAGEN THAT ACTS BY INHIBITING MISMATCH REPAIR. MOST ERRORS THAT ARISE DURING DNA REPLICATION CAN BE CORRECTED BY DNA POLYMERASE PROOFREADING OR BY POST-REPLICATION MISMATCH REPAIR (MMR). INACTIVATION OF BOTH MUTATION-AVOIDANCE SYSTEMS RESULTS IN EXTREMELY HIGH MUTABILITY THAT CAN LEAD TO ERROR CATASTROPHE. HIGH MUTABILITY AND THE LIKELIHOOD OF CANCER CAN BE CAUSED BY MUTATIONS AND EPIGENETIC CHANGES THAT REDUCE MMR. HYPERMUTABILITY CAN ALSO BE CAUSED BY EXTERNAL FACTORS THAT DIRECTLY INHIBIT MMR. IDENTIFYING SUCH FACTORS HAS IMPORTANT IMPLICATIONS FOR UNDERSTANDING THE ROLE OF THE ENVIRONMENT IN GENOME STABILITY. WE FOUND THAT CHRONIC EXPOSURE OF YEAST TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF CADMIUM, A KNOWN HUMAN CARCINOGEN, CAN RESULT IN EXTREME HYPERMUTABILITY. THE MUTATION SPECIFICITY ALONG WITH RESPONSES IN PROOFREADING-DEFICIENT AND MMR-DEFICIENT MUTANTS INDICATE THAT CADMIUM REDUCES THE CAPACITY FOR MMR OF SMALL MISALIGNMENTS AND BASE-BASE MISMATCHES. IN EXTRACTS OF HUMAN CELLS, CADMIUM INHIBITED AT LEAST ONE STEP LEADING TO MISMATCH REMOVAL. TOGETHER, OUR DATA SHOW THAT A HIGH LEVEL OF GENETIC INSTABILITY CAN RESULT FROM ENVIRONMENTAL IMPEDIMENT OF A MUTATION-AVOIDANCE SYSTEM.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 6294  23 THE PROINFLAMMATORY CYTOKINE TNFALPHA INDUCES DNA DEMETHYLATION-DEPENDENT AND -INDEPENDENT ACTIVATION OF INTERLEUKIN-32 EXPRESSION. IL-32 IS A CYTOKINE INVOLVED IN PROINFLAMMATORY IMMUNE RESPONSES TO BACTERIAL AND VIRAL INFECTIONS. HOWEVER, THE ROLE OF EPIGENETIC EVENTS IN THE REGULATION OF IL-32 GENE EXPRESSION IS UNDERSTUDIED. HERE WE SHOW THAT IL-32 IS REPRESSED BY DNA METHYLATION IN HEK293 CELLS. USING CHIP SEQUENCING, LOCUS-SPECIFIC METHYLATION ANALYSIS, CRISPR/CAS9-MEDIATED GENOME EDITING, AND RT-QPCR (QUANTITATIVE RT-PCR) AND IMMUNOBLOT ASSAYS, WE FOUND THAT SHORT-TERM TREATMENT (A FEW HOURS) WITH THE PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) ACTIVATES IL-32 IN A DNA DEMETHYLATION-INDEPENDENT MANNER. IN CONTRAST, PROLONGED TNFALPHA TREATMENT (SEVERAL DAYS) INDUCED DNA DEMETHYLATION AT THE PROMOTER AND A CPG ISLAND IN THE IL-32 GENE IN A TET (TEN-ELEVEN TRANSLOCATION) FAMILY ENZYME- AND NF-KAPPAB-DEPENDENT MANNER. NOTABLY, THE HYPOMETHYLATION STATUS OF TRANSCRIPTIONAL REGULATORY ELEMENTS IN IL-32 WAS MAINTAINED FOR A LONG TIME (SEVERAL WEEKS), CAUSING ELEVATED IL-32 EXPRESSION EVEN IN THE ABSENCE OF TNFALPHA. CONSIDERING THAT IL-32 CAN, IN TURN, INDUCE TNFALPHA EXPRESSION, WE SPECULATE THAT SUCH FEEDFORWARD EVENTS MAY CONTRIBUTE TO THE TRANSITION FROM AN ACUTE INFLAMMATORY RESPONSE TO CHRONIC INFLAMMATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5 2453  30 EPIGENETIC SUPPRESSION OF THE IMMUNOREGULATOR MZB1 IS ASSOCIATED WITH THE MALIGNANT PHENOTYPE OF GASTRIC CANCER. PREDICTION OF TUMOR RECURRENCE AFTER CURATIVE RESECTION IS CRITICAL FOR DETERMINING THE PROGNOSIS OF PATIENTS WITH GASTRIC CANCER (GC). THE INITIATION AND PROGRESSION OF GC ARE ASSOCIATED WITH INAPPROPRIATE IMMUNE RESPONSES CAUSED BY CHRONIC INFLAMMATION OF THE GASTRIC MUCOSA. TO IDENTIFY IMMUNOREGULATORY MOLECULES INVOLVED IN GC PROGRESSION, GC CELL LINES AND 200 PAIRS OF TUMOR AND NORMAL TISSUES FROM PATIENTS WITH GC WERE ANALYZED FOR GENE EXPRESSION, AMPLIFICATION AND METHYLATION AS WELL AS FUNCTION OF A DIFFERENTIALLY EXPRESSED GENE. THE TRANSCRIPTOME ANALYSIS REVEALED THAT MARGINAL ZONE B AND B1 CELL SPECIFIC PROTEIN (MZB1) WAS EXPRESSED AT SIGNIFICANTLY DECREASED LEVELS IN PRIMARY GC TISSUES WHEN COMPARED WITH THE CORRESPONDING NORMAL GASTRIC MUCOSA. PCR ARRAY ANALYSIS EXPLORING GENES EXPRESSED COOPERATIVELY WITH MZB1 REVEALED THAT DIFFERENTIAL EXPRESSION OF MZB1 MRNA IN GC CELL LINES CORRELATED POSITIVELY WITH THE LEVELS OF THE MRNAS ENCODING ESTROGEN RECEPTOR 1 AND DESUMOYLATING ISOPEPTIDASE 1. HYPERMETHYLATION OF THE MZB1 PROMOTER WAS FREQUENT IN CELL LINES WITH DECREASED LEVELS OF MZB1 MRNA. SIRNA-MEDIATED KNOCKDOWN OF MZB1 SIGNIFICANTLY INCREASED PROLIFERATION, INVASION AND MIGRATION OF GC CELL LINES. LOW MZB1 EXPRESSION WAS AN INDEPENDENT PROGNOSTIC FACTOR FOR RECURRENCE AFTER CURATIVE GASTRECTOMY AND WAS ASSOCIATED SIGNIFICANTLY WITH INCREASED HEMATOGENOUS RECURRENCE. MZB1 ACTS AS A SUPPRESSOR OF GC. LOW MZB1 EXPRESSION IN THE PRIMARY GC TISSUE IS PREDICTIVE OF RECURRENCE AFTER CURATIVE RESECTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6 3468  36 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA.	2012	
                                                                  
7 2395  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  136  34 ABERRANT DNA HYPERMETHYLATION PATTERNS LEAD TO TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS OF MICE. OVEREXPOSURE OF THE HUMAN SKIN TO SOLAR ULTRAVIOLET (UV) RADIATION IS THE MAJOR ETIOLOGIC FACTOR FOR DEVELOPMENT OF SKIN CANCERS. HERE, WE REPORT THE RESULTS OF EPIGENETIC MODIFICATIONS IN UV-EXPOSED SKIN AND SKIN TUMORS IN A SYSTEMATIC MANNER. THE SKIN AND TUMOR SAMPLES WERE COLLECTED AFTER CHRONIC EXPOSURE OF THE SKIN OF SKH-1 HAIRLESS MICE TO UVB RADIATION USING A WELL-ESTABLISHED PHOTOCARCINOGENESIS PROTOCOL. WE FOUND A DISTINCT DNA HYPERMETHYLATION PATTERN IN THE UVB-EXPOSED EPIDERMAL SKIN AND UVB-INDUCED SKIN TUMORS THAT WAS ASSOCIATED WITH THE ELEVATED EXPRESSION AND ACTIVITY OF THE DNA METHYLTRANSFERASES (DNMT) 1, DNMT3A AND DNMT3B. TO EXPLORE THE ROLE OF HYPERMETHYLATION IN SKIN PHOTOCARCINOGENESIS, WE FOCUSED ON THE P16(INK4A) AND RASSF1A TUMOR SUPPRESSOR GENES, WHICH ARE TRANSCRIPTIONALLY SILENCED ON METHYLATION. WE ESTABLISHED THAT THE SILENCING OF THESE GENES IN UVB-EXPOSED EPIDERMIS AND UVB-INDUCED SKIN TUMORS IS ASSOCIATED WITH A NETWORK OF EPIGENETIC MODIFICATIONS, INCLUDING HYPOACETYLATION OF HISTONE H3 AND H4 AND INCREASED HISTONE DEACETYLATION, AS WELL AS RECRUITMENT OF METHYL-BINDING PROTEINS, INCLUDING MECP2 AND MBD1, TO THE METHYLATED CPGS. HIGHER LEVELS OF DNA METHYLATION AND DNMT ACTIVITY IN HUMAN SQUAMOUS CELL CARCINOMA SPECIMENS THAN IN NORMAL HUMAN SKIN SUGGEST THAT THE DATA ARE RELEVANT CLINICALLY. OUR DATA INDICATE FOR THE FIRST TIME THAT UVB-INDUCED DNA HYPERMETHYLATION, ENHANCED DNMT ACTIVITY AND HISTONE MODIFICATIONS OCCUR IN UVB-EXPOSED SKIN AND UVB-INDUCED SKIN TUMORS AND SUGGEST THAT THESE EVENTS ARE INVOLVED IN THE SILENCING OF TUMOR SUPPRESSOR GENES AND IN SKIN TUMOR DEVELOPMENT.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 3718  31 INHIBITION OF BCL6B PROMOTES GASTRIC CANCER BY AMPLIFYING INFLAMMATION IN MICE. BACKGROUND: CHRONIC GASTRITIS HAS BEEN DEMONSTRATED TO BE A KEY CAUSE OF GASTRIC CANCER (GC), AND CONTROL OF GASTRIC INFLAMMATION IS REGARDED AS AN EFFECTIVE TREATMENT FOR THE CLINICAL PREVENTION OF GASTRIC CARCINOGENESIS. HOWEVER, THERE REMAINS AN UNMET NEED TO IDENTIFY THE DOMINANT REGULATORS OF GASTRIC ONCOGENESIS-ASSOCIATED INFLAMMATION IN VIVO. METHODS: THE MOUSE MODEL FOR THE STUDY OF INFLAMMATION-ASSOCIATED GC WAS INDUCED BY BENZO[A]PYRENE (BAP) INTRAGASTRIC ADMINISTRATION IN BCL6B(-/-) AND WILDTYPE MICE ON A C57BL/6 BACKGROUND. 5-AZA-2'-DEOXYCYTIDINE (5-AZA), THE DEMETHYLATION DRUG, WAS INTRAPERITONEALLY INJECTED TO RESTORE BCL6B EXPRESSION. HUMAN GC TISSUE ARRAY WAS USED TO ANALYSE PATIENT SURVIVAL BASED ON BCL6B AND CD3 PROTEIN EXPRESSION. RESULTS: BCL6B WAS GRADUALLY DOWNREGULATED BY ITS OWN PROMOTER HYPERMETHYLATION IN PARALLEL TO AN INCREASING INFLAMMATORY RESPONSE DURING THE PROGRESSION OF BAP-INDUCED GASTRIC CARCINOGENESIS IN MICE. MOREOVER, KNOCKOUT OF BCL6B DRAMATICALLY WORSENED THE SEVERITY OF GASTRIC CANCER AND AGGRAVATED THE INFLAMMATORY RESPONSE IN THE BAP-INDUCED MICE GC MODEL. RE-ACTIVATION OF BCL6B BY 5-AZA IMPEDED INFLAMMATORY AMPLIFICATION AND BAP-INDUCED GC DEVELOPMENT, PROLONGING SURVIVAL TIME IN WILDTYPE MICE, WHEREAS NO NOTABLE CURATIVE EFFECT OCCURRED IN BCL6B(-/-) MICE WITH 5-AZA TREATMENT. FINALLY, SIGNIFICANT NEGATIVE CORRELATIONS WERE DETECTED BETWEEN THE MRNA LEVELS OF BCL6B AND INFLAMMATORY CYTOKINES IN HUMAN GC TISSUES; PATIENTS HARBOURING BCL6B-NEGETIVE AND SEVERE-INFLAMMATION GC TUMOURS WERE FOUND TO EXHIBIT THE SHORTEST SURVIVAL TIME. CONCLUSIONS: EPIGENETIC INACTIVATION OF BCL6B PROMOTES GASTRIC CANCER THROUGH AMPLIFICATION OF THE GASTRIC INFLAMMATORY RESPONSE IN VIVO AND OFFERS A NEW APPROACH FOR GC TREATMENT AND REGENERATIVE MEDICINE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
10 1334  29 DEREGULATION OF AIOLOS EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE NEOPLASTIC B CELLS THAT ARE RESISTANT TO APOPTOSIS. AIOLOS, A MEMBER OF THE IKAROS FAMILY OF ZINC-FINGER TRANSCRIPTION FACTORS, PLAYS AN IMPORTANT ROLE IN THE CONTROL OF MATURE B LYMPHOCYTE DIFFERENTIATION AND MATURATION. IN THIS STUDY, WE SHOWED THAT AIOLOS EXPRESSION IS UP-REGULATED IN B-CLL CELLS. THIS OVEREXPRESSION DOES NOT IMPLICATE ISOFORM IMBALANCE OR DISTURB AIOLOS SUBCELLULAR LOCALIZATION. THE CHROMATIN STATUS AT THE AIOLOS PROMOTER IN CLL IS DEFINED BY THE DEMETHYLATION OF DNA AND AN ENRICHMENT OF EUCHROMATIN ASSOCIATED HISTONE MARKERS, SUCH AS THE DIMETHYLATION OF THE LYSINE 4 ON HISTONE H3. THESE EPIGENETIC MODIFICATIONS SHOULD ALLOW ITS UPSTREAM EFFECTORS, SUCH AS NUCLEAR FACTOR-KAPPAB, CONSTITUTIVELY ACTIVATED IN CLL, TO GAIN ACCESS TO PROMOTER, RESULTING UP-REGULATION OF AIOLOS. TO DETERMINE THE CONSEQUENCES OF AIOLOS DEREGULATION IN CLL, WE ANALYZED THE EFFECTS OF AIOLOS OVEREXPRESSION OR DOWN-REGULATION ON APOPTOSIS. AIOLOS IS INVOLVED IN CELL SURVIVAL BY REGULATING THE EXPRESSION OF SOME BCL-2 FAMILY MEMBERS. OUR RESULTS STRONGLY SUGGEST THAT AIOLOS DEREGULATION BY EPIGENETIC MODIFICATIONS MAY BE A HALLMARK OF CLL.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  402  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 5101  25 POLYCOMB FACTOR PHF19 CONTROLS CELL GROWTH AND DIFFERENTIATION TOWARD ERYTHROID PATHWAY IN CHRONIC MYELOID LEUKEMIA CELLS. POLYCOMB GROUP (PCG) OF PROTEINS ARE A GROUP OF HIGHLY CONSERVED EPIGENETIC REGULATORS INVOLVED IN MANY BIOLOGICAL FUNCTIONS, SUCH AS EMBRYONIC DEVELOPMENT, CELL PROLIFERATION, AND ADULT STEM CELL DETERMINATION. PHD FINGER PROTEIN 19 (PHF19) IS AN ASSOCIATED FACTOR OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2), OFTEN UPREGULATED IN HUMAN CANCERS. IN PARTICULAR, MYELOID LEUKEMIA CELL LINES SHOW INCREASED LEVELS OF PHF19, YET LITTLE IS KNOWN ABOUT ITS FUNCTION. HERE, WE HAVE CHARACTERIZED THE ROLE OF PHF19 IN MYELOID LEUKEMIA CELLS. WE DEMONSTRATED THAT PHF19 DEPLETION DECREASES CELL PROLIFERATION AND PROMOTES CHRONIC MYELOID LEUKEMIA (CML) DIFFERENTIATION. MECHANISTICALLY, WE HAVE SHOWN HOW PHF19 REGULATES THE PROLIFERATION OF CML THROUGH A DIRECT REGULATION OF THE CELL CYCLE INHIBITOR P21. FURTHERMORE, WE OBSERVED THAT MTF2, A PHF19 HOMOLOG, PARTIALLY COMPENSATES FOR PHF19 DEPLETION IN A SUBSET OF TARGET GENES, INSTRUCTING SPECIFIC ERYTHROID DIFFERENTIATION. TAKEN TOGETHER, OUR RESULTS SHOW THAT PHF19 IS A KEY TRANSCRIPTIONAL REGULATOR FOR CELL FATE DETERMINATION AND COULD BE A POTENTIAL THERAPEUTIC TARGET FOR MYELOID LEUKEMIA TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13 5871  27 SUSTAINED NF-KAPPAB ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA IS INDEPENDENT OF GENETIC AND EPIGENETIC ALTERATIONS IN THE TNFAIP3 (A20) LOCUS. INAPPROPRIATE NUCLEAR FACTOR (NF) KAPPAB ACTIVITY IS ONE MAJOR HALLMARK OF B-CELL MALIGNANCIES AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). NFKAPPAB-DEPENDENT GENES ARE INVOLVED IN ANTIAPOPTOSIS, CELL PROLIFERATION AND METASTASIS AND ARE RESPONSIBLE FOR SURVIVAL AND PROLIFERATION OF TUMORS. HOWEVER, THE MECHANISMS OF NFKAPPAB ACTIVITY IN CLL STILL NEED TO BE ELUCIDATED. PREVIOUSLY, WE IDENTIFIED TRANSLOCATIONS IN A REGION ON CHROMOSOME 6Q THAT ENCODES TUMOR NECROSIS FACTOR ALPHA-INDUCED PROTEIN 3, WHICH IS A KEY PLAYER IN NEGATIVE FEEDBACK LOOP REGULATION OF NFKAPPAB. INACTIVATION OF THIS UBIQUITIN-EDITING ENZYME IS INVOLVED IN IMMUNOPATHOLOGIES AND IN TUMORIGENESIS. FREQUENT MUTATIONS IN THE A20 LOCUS--LEADING TO SUSTAINED NFKAPPAB ACTIVITY--COULD BE SHOWN TO PLAY A DOMINANT ROLE IN DEVELOPMENT OF DIFFERENT B-CELL MALIGNANCIES. TO CHECK IF A20 IS INVOLVED IN UPREGULATION OF NFKAPPAB ACTIVITY IN CLL, WE SEQUENCED EXONS 2-9 OF THE A20 GENE IN 55 CLL DNA SAMPLES. FURTHERMORE, WE DETERMINED THE METHYLATION STATUS OF THE PROMOTER REGION IN 63 CLL DNA SAMPLES AND COMPARED TO 10 CONTROL DNAS OF B CELLS FROM HEALTHY DONORS. CONTRARY TO REPORTS FROM OTHER B-CELL MALIGNANCIES, THE A20 REGION SHOWED NEITHER MUTATIONS NOR ABERRANT DNA METHYLATION. MOREOVER, ITS EXPRESSION COULD BE CONFIRMED BY IMMUNOBLOTTING AND SHOWING COMPARABLE RESULTS TO HEALTHY B CELLS. THESE RESULTS INDICATE THAT MALIGNANT DEVELOPMENT IN CLL DIFFERS FROM MOST OF OTHER B-CELL MALIGNANCIES, WHICH SHOW FREQUENT INACTIVATION OF A20.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 2637  30 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	

15  499  35 ASSOCIATION BETWEEN HMLH1 HYPERMETHYLATION AND JC VIRUS (JCV) INFECTION IN HUMAN COLORECTAL CANCER (CRC). INCORPORATION OF VIRAL DNA MAY INTERFERE WITH THE NORMAL SEQUENCE OF HUMAN DNA BASES ON THE GENETIC LEVEL OR CAUSE SECONDARY EPIGENETIC CHANGES SUCH AS GENE PROMOTER METHYLATION OR HISTONE ACETYLATION. COLORECTAL CANCER (CRC) IS THE SECOND LEADING CAUSE OF CANCER MORTALITY IN THE USA. CHROMOSOMAL INSTABILITY (CIN) WAS ESTABLISHED AS THE KEY MECHANISM IN CANCER DEVELOPMENT. LATER, IT WAS FOUND THAT CRC RESULTS NOT ONLY FROM THE PROGRESSIVE ACCUMULATION OF GENETIC ALTERATIONS BUT ALSO FROM EPIGENETIC CHANGES. JC VIRUS (JCV) IS A CANDIDATE ETIOLOGIC FACTOR IN SPORADIC CRC. IT MAY ACT BY STABILIZING BETA-CATENIN, FACILITATING ITS ENTRANCE TO THE CELL NUCLEUS, INITIALING PROLIFERATION AND CANCER DEVELOPMENT. DIPLOID CRC CELL LINES TRANSFECTED WITH JCV-CONTAINING PLASMIDS DEVELOPED CIN. THIS RESULT PROVIDES DIRECT EXPERIMENTAL EVIDENCE FOR THE ABILITY OF JCV T-AG TO INDUCE CIN IN THE GENOME OF COLONIC EPITHELIAL CELLS. THE ASSOCIATION OF CRC HMLH1 METHYLATION AND TUMOR POSITIVITY FOR JCV WAS RECENTLY DOCUMENTED. JC VIRUS T-AG DNA SEQUENCES WERE FOUND IN 77% OF CRCS AND ARE ASSOCIATED WITH PROMOTER METHYLATION OF MULTIPLE GENES. HMLH1 WAS METHYLATED IN 25 OUT OF 80 CRC PATIENTS POSITIVE FOR T-AG (31%) IN COMPARISON WITH ONLY ONE OUT OF 11 T-AG NEGATIVE CASES (9%). THUS, JCV CAN MEDIATE BOTH CIN AND ABERRANT METHYLATION IN CRC. LIKE OTHER VIRUSES, CHRONIC INFECTION WITH JCV MAY INDUCE CRC BY DIFFERENT MECHANISMS WHICH SHOULD BE FURTHER INVESTIGATED. THUS, GENE PROMOTER METHYLATION INDUCED BY JCV MAY BE AN IMPORTANT PROCESS IN CRC AND THE POLYP-CARCINOMA SEQUENCE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 3195  31 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	
                                                                                                                                                                                                                                                                                                                 
17 3049  24 GENOME-WIDE ANALYSIS REVEALS ZINC TRANSPORTER ZIP9 REGULATED BY DNA METHYLATION PROMOTES RADIATION-INDUCED SKIN FIBROSIS VIA THE TGF-BETA SIGNALING PATHWAY. RADIATION-INDUCED SKIN FIBROSIS IS A DETRIMENTAL AND CHRONIC DISORDER THAT OCCURS AFTER RADIATION EXPOSURE. DNA METHYLATION HAS BEEN CHARACTERIZED AS AN IMPORTANT REGULATORY MECHANISM OF MULTIPLE PATHOLOGICAL PROCESSES. IN THIS STUDY, WE COMPARED THE GENOME-WIDE DNA METHYLATION STATUS IN RADIATION-INDUCED FIBROTIC SKIN AND ADJACENT NORMAL TISSUES OF RATS BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. RADIATION-INDUCED FIBROTIC SKIN SHOWED DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH 3,650 PROTEIN-CODING GENES, 72 MICRORNAS, 5,836 LONG NONCODING RNAS AND 3 PIWI-INTERACTING RNAS. BY INTEGRATING THE MRNA AND METHYLATION PROFILES, THE ZINC TRANSPORTER SLC39A9/ZIP9 WAS INVESTIGATED IN GREATER DETAIL. THE PROTEIN LEVEL OF ZIP9 WAS INCREASED IN IRRADIATED SKIN TISSUES OF HUMANS, MONKEYS, AND RATS, ESPECIALLY IN RADIOGENIC FIBROTIC SKIN TISSUES. RADIATION INDUCED THE DEMETHYLATION OF A CPG DINUCLEOTIDE IN EXON 1 OF ZIP9 THAT RESULTED IN RECRUITMENT OF THE TRANSCRIPTIONAL FACTOR SP1 AND INCREASED ZIP9 EXPRESSION. OVEREXPRESSION OF ZIP9 RESULTED IN ACTIVATION OF THE PROFIBROTIC TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY THROUGH PROTEIN KINASE B IN HUMAN FIBROBLASTS. IN ADDITION, RADIATION-INDUCED SKIN FIBROSIS WAS ASSOCIATED WITH INCREASED ZINC ACCUMULATION. THE ZINC CHELATOR N,N,N',N'-TETRAKIS(2-PYRIDYLMETHYL)-1,2-ETHYLENEDIAMINE ABROGATED ZIP9-INDUCED ACTIVATION OF THE TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY AND ATTENUATED RADIATION-INDUCED SKIN FIBROSIS IN A RAT MODEL. IN SUMMARY, OUR FINDINGS ILLUSTRATE EPIGENETIC REGULATION OF ZIP9 AND ITS CRITICAL ROLE IN PROMOTING RADIATION-INDUCED SKIN FIBROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 1293  28 DECREASED ERK AND JNK SIGNALING CONTRIBUTE TO GENE OVEREXPRESSION IN "SENESCENT" CD4+CD28- T CELLS THROUGH EPIGENETIC MECHANISMS. AN INFLAMMATORY AND CYTOTOXIC CD4+CD28- T CELL SUBSET INFILTRATES ATHEROSCLEROTIC PLAQUES AND IS IMPLICATED IN PLAQUE RUPTURE AND MYOCARDIAL INFARCTIONS. THIS PATHOLOGIC SUBSET DEVELOPS WITH REPLICATIVE STRESS AND IS FOUND IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES SUCH AS RA AS WELL AS WITH AGING. CD4+CD28- CELLS OVEREXPRESS GENES NORMALLY SUPPRESSED BY DNA METHYLATION IN CD4+CD28+ T CELLS, SUCH AS KIR, PERFORIN, AND CD70. HOW THIS SUBSET OVER EXPRESSES METHYLATION-SENSITIVE GENES IS UNKNOWN. DNA METHYLATION PATTERNS ARE MAINTAINED IN PROLIFERATING CELLS BY DNMTS, WHICH ARE UP-REGULATED DURING MITOSIS BY THE ERK AND JNK SIGNALING PATHWAYS. WE HYPOTHESIZED THAT DEFECTS IN THESE SIGNALING PATHWAYS CONTRIBUTE TO ALTERED GENE EXPRESSION IN HUMAN CD4+CD28- CELLS THROUGH EFFECTS ON DNA METHYLATION. WE REPORT THAT SIGNALING THROUGH THE ERK AND JNK PATHWAYS IS DECREASED IN CD4+CD28- RELATIVE TO CD4+CD28+ CELLS FROM THE SAME INDIVIDUALS AND THAT ERK AND JNK PATHWAY INHIBITION DECREASES DNMT1 AND -3A LEVELS, WHICH IN TURN, CAUSES DEMETHYLATION AND OVEREXPRESSION OF THE TNFSF7 (CD70) GENE. WE ALSO REPORT THAT CD4+CD28- T CELLS OVEREXPRESS PP5, A STRESS-INDUCED INHIBITOR OF THE ERK AND JNK SIGNALING PATHWAYS THAT MAY CONTRIBUTE TO THE SIGNALING DEFECTS. WE CONCLUDE THAT DECREASED ERK AND JNK SIGNALING IN THE CD4+CD28- SUBSET, ARISING WITH REPLICATIVE STRESS, CAN LEAD TO THE OVEREXPRESSION OF NORMALLY SUPPRESSED GENES THROUGH EFFECTS ON DNMTS AND CONSEQUENTLY, CHROMATIN STRUCTURE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19 4221  27 METHYLATION AND SILENCING OF PROTEIN TYROSINE PHOSPHATASE RECEPTOR TYPE O IN CHRONIC LYMPHOCYTIC LEUKEMIA. PURPOSE: PREVIOUS STUDIES IN OUR LABORATORY HAVE SHOWN THE PROGRESSIVE METHYLATION AND SUPPRESSION OF THE GENE ENCODING PROTEIN TYROSINE PHOSPHATASE, PTPRO, IN THE LIVERS OF RATS FED A METHYL-DEFICIENT DIET THAT INDUCES HEPATOCARCINOGENESIS. SUBSEQUENTLY, WE OBSERVED THE METHYLATION OF PTPRO IN PRIMARY HUMAN LUNG TUMORS AND ALSO SHOWED ITS POTENTIAL TUMOR SUPPRESSOR CHARACTERISTICS. THE PRESENT STUDY WAS UNDERTAKEN TO INVESTIGATE WHETHER THE TRUNCATED FORM OF PTPRO (PTPROT), SPECIFICALLY EXPRESSED IN NAIVE B LYMPHOCYTES, WAS ALSO METHYLATED AND SUPPRESSED IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A DISEASE GENERALLY AFFECTING B LYMPHOCYTES. EXPERIMENTAL DESIGN AND RESULTS: INITIAL SCREENING SHOWED THAT 60% OF THE 52 CLL SAMPLES ANALYZED USING METHYLATION-SPECIFIC PCR ASSAY WERE METHYLATED COMPARED WITH B LYMPHOCYTES FROM NORMAL INDIVIDUALS, WHICH WERE NOT METHYLATED. THE EXPRESSION OF PTPROT, AS MEASURED BY SEMIQUANTITATIVE REVERSE TRANSCRIPTION-PCR, INVERSELY CORRELATED WITH METHYLATION IN THE FEW SAMPLES TESTED. ANALYSIS OF ADDITIONAL SAMPLES (N = 50) BY COMBINED BISULFITE RESTRICTION ANALYSIS SHOWED THAT THE PTPRO CPG ISLAND WAS METHYLATED IN 82% OF PATIENTS WITH CLL COMPARED WITH B LYMPHOCYTES FROM NORMAL INDIVIDUALS. FURTHERMORE, OVERALL EXPRESSION OF PTPRO WAS REDUCED IN CLL RELATIVE TO NORMAL LYMPHOCYTES. THE PTPRO GENE WAS ALSO SUPPRESSED BY METHYLATION IN THE CLL CELL LINE WAC3CD5, WHERE IT COULD BE REACTIVATED UPON TREATMENT WITH THE DNA HYPOMETHYLATING AGENT 5-AZAC. ECTOPIC EXPRESSION OF PTPROT IN A NONEXPRESSING CELL LINE INCREASED GROWTH INHIBITION WITH FLUDARABINE TREATMENT, A THERAPY COMMONLY USED FOR CLL. CONCLUSION: THIS STUDY REVEALS THE POTENTIAL ROLE OF PTPRO METHYLATION AND SILENCING IN CLL TUMORIGENESIS AND ALSO PROVIDES A NOVEL MOLECULAR TARGET IN THE EPIGENETIC THERAPY.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                 
20  164  33 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET.	2012