1 902 122 CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION CAUSES INCREASED GROWTH AND TRANSFORMATION IN HUMAN PROSTATE EPITHELIAL CELLS POTENTIALLY BY HYPERMETHYLATION-MEDIATED SILENCING OF MLH1. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN IS ASSOCIATED WITH RISK OF PROSTATE CANCER, BUT THEIR MECHANISM IS NOT FULLY UNDERSTOOD. ADDITIONALLY, THE CARCINOGENIC EFFECTS OF THEIR CO-EXPOSURE ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION, ON CELL GROWTH AND TRANSFORMATION, AND IDENTIFY THE MECHANISM BEHIND THESE EFFECTS. METHODS: RWPE-1 HUMAN PROSTATE EPITHELIAL CELLS WERE CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION. CELL GROWTH WAS MEASURED BY CELL COUNT AND CELL CYCLE, WHEREAS CELL TRANSFORMATION WAS EVALUATED BY COLONY FORMATION ASSAY. GENE EXPRESSION WAS MEASURED BY QUANTITATIVE REAL-TIME PCR AND CONFIRMED AT PROTEIN LEVEL BY WESTERN BLOT ANALYSIS. MLH1 PROMOTER METHYLATION WAS DETERMINED BY PYROSEQUENCING METHOD. RESULTS: EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATIONS INCREASES CELL GROWTH AND TRANSFORMATION IN RWPE-1 CELLS. INCREASED EXPRESSION OF CYCLIN D1 AND BCL2, WHEREAS DECREASED EXPRESSION OF MISMATCH REPAIR GENES MSH4, MSH6, AND MLH1 WAS ALSO OBSERVED. HYPERMETHYLATION OF MLH1 PROMOTER FURTHER SUGGESTED THE EPIGENETIC INACTIVATION OF MLH1 EXPRESSION IN ARSENIC AND ESTROGEN TREATED CELLS. ARSENIC AND ESTROGEN COMBINATION CAUSED GREATER CHANGES THAN THEIR INDIVIDUAL TREATMENTS. CONCLUSIONS: FINDINGS OF THIS STUDY FOR THE FIRST TIME SUGGEST THAT ARSENIC AND ESTROGEN EXPOSURES CAUSE INCREASED CELL GROWTH AND SURVIVAL POTENTIALLY THROUGH EPIGENETIC INACTIVATION OF MLH1 RESULTING IN DECREASED MLH1-MEDIATED APOPTOTIC RESPONSE, AND CONSEQUENTLY INCREASED CELLULAR TRANSFORMATION. 2013 2 1815 58 EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN ON EPIGENETIC REGULATORY GENES EXPRESSION AND EPIGENETIC CODE IN HUMAN PROSTATE EPITHELIAL CELLS. CHRONIC EXPOSURES TO ARSENIC AND ESTROGEN ARE KNOWN RISK FACTORS FOR PROSTATE CANCER. THOUGH THE EVIDENCE SUGGESTS THAT EXPOSURE TO ARSENIC OR ESTROGENS CAN DISRUPT NORMAL DNA METHYLATION PATTERNS AND HISTONE MODIFICATIONS, THE MECHANISMS BY WHICH THESE CHEMICALS INDUCE EPIGENETIC CHANGES ARE NOT FULLY UNDERSTOOD. MOREOVER, THE EPIGENETIC EFFECTS OF CO-EXPOSURE TO THESE TWO CHEMICALS ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN, BOTH ALONE AND IN COMBINATION, ON THE EXPRESSION OF EPIGENETIC REGULATORY GENES, THEIR CONSEQUENCES ON DNA METHYLATION, AND HISTONE MODIFICATIONS. HUMAN PROSTATE EPITHELIAL CELLS, RWPE-1, CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION WERE USED FOR ANALYSIS OF EPIGENETIC REGULATORY GENES EXPRESSION, GLOBAL DNA METHYLATION CHANGES, AND HISTONE MODIFICATIONS AT PROTEIN LEVEL. THE RESULT OF THIS STUDY REVEALED THAT EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION ALTERS THE EXPRESSION OF EPIGENETIC REGULATORY GENES AND CHANGES GLOBAL DNA METHYLATION AND HISTONE MODIFICATION PATTERNS IN RWPE-1 CELLS. THESE CHANGES WERE SIGNIFICANTLY GREATER IN ARSENIC AND ESTROGEN COMBINATION TREATED GROUP THAN INDIVIDUALLY TREATED GROUP. THE FINDINGS OF THIS STUDY WILL HELP EXPLAIN THE EPIGENETIC MECHANISM OF ARSENIC- AND/OR ESTROGEN-INDUCED PROSTATE CARCINOGENESIS. 2012 3 978 57 CHRONIC OXIDATIVE STRESS CAUSES ESTROGEN-INDEPENDENT AGGRESSIVE PHENOTYPE, AND EPIGENETIC INACTIVATION OF ESTROGEN RECEPTOR ALPHA IN MCF-7 BREAST CANCER CELLS. THE ROLE OF CHRONIC OXIDATIVE STRESS IN THE DEVELOPMENT AND AGGRESSIVE GROWTH OF ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER IS WELL KNOWN; HOWEVER, THE MECHANISTIC UNDERSTANDING IS NOT CLEAR. ESTROGEN-INDEPENDENT GROWTH IS ONE OF THE FEATURES OF AGGRESSIVE SUBTYPE OF BREAST CANCER. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECT OF OXIDATIVE STRESS ON ESTROGEN SENSITIVITY AND EXPRESSION OF NUCLEAR ESTROGEN RECEPTORS IN ER-POSITIVE BREAST CANCER CELLS. MCF-7 CELLS CHRONICALLY EXPOSED TO HYDROGEN PEROXIDE WERE USED AS A CELL MODEL IN THIS STUDY, AND THEIR GROWTH IN RESPONSE TO 17-BETA ESTRADIOL WAS EVALUATED BY CELL VIABILITY, CELL CYCLE, AND CELL MIGRATION ANALYSIS. RESULTS WERE FURTHER CONFIRMED AT MOLECULAR LEVEL BY ANALYSIS OF GENE EXPRESSIONS AT TRANSCRIPT AND PROTEIN LEVELS. HISTONE H3 MODIFICATIONS, EXPRESSION OF EPIGENETIC REGULATORY GENES, AND THE EFFECT OF DNA DEMETHYLATION WERE ALSO ANALYZED. LOSS OF GROWTH IN RESPONSE TO ESTROGEN WITH A DECREASE IN ERALPHA EXPRESSION WAS OBSERVED IN MCF-7 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. INCREASES IN MTTFA AND NRF1 IN THESE CELLS FURTHER SUGGESTED THE ROLE OF MITOCHONDRIA-DEPENDENT REDOX-SENSITIVE GROWTH SIGNALING AS AN ALTERNATIVE PATHWAY TO ESTROGEN-DEPENDENT GROWTH. CHANGES IN EXPRESSION OF EPIGENETIC REGULATORY GENES, LEVELS OF HISTONE H3 MODIFICATIONS AS WELL AS SIGNIFICANT RESTORATIONS OF BOTH ERALPHA EXPRESSION AND ESTROGEN RESPONSE BY 5-AZA-2'-DEOXYCYTIDINE FURTHER CONFIRMED THE EPIGENETIC BASIS FOR ESTROGEN-INDEPENDENT GROWTH IN THESE CELLS. IN CONCLUSION, RESULTS OF THIS STUDY SUGGEST THAT CHRONIC OXIDATIVE STRESS CAN CONVERT ESTROGEN-DEPENDENT NONAGGRESSIVE BREAST CANCER CELLS INTO ESTROGEN-INDEPENDENT AGGRESSIVE FORM POTENTIALLY BY EPIGENETIC MECHANISM. 2015 4 3795 37 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 5 5276 38 PROMOTER METHYLATION OF TUMOR-RELATED GENES IN GASTRIC CARCINOGENESIS. ABERRANT PROMOTER METHYLATION AND SUBSEQUENT SILENCING OF CANCER-RELATED GENES HAS BEEN RECOGNIZED AS AN IMPORTANT PATHWAY INVOLVED IN GASTRIC CARCINOGENESIS. IN FACT, SEVERAL FACTORS ARE BELIEVED TO CONTRIBUTE TO ITS INDUCTION IN GASTRIC EPITHELIA, INCLUDING AGING, DIET, CHRONIC INFLAMMATION AND INFECTION OF HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV). HOWEVER, THE UNDERLING MECHANISMS ARE NOT COMPLETELY IDENTIFIED, DESPITE THE BELIEF THAT INCREASED EXPRESSION OR ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), OR DECREASED DEMETHYLATION ACTIVITY MAY CONTRIBUTE TO THE EXCESSIVE METHYLATION. A GREAT NUMBER OF GENES WITH PROMOTER METHYLATION HAVE BEEN OBSERVED IN GASTRIC CANCER (GC), AMONG WHICH P16INK4A (P16), MUT L HOMOLOGUE 1 (MLH1), EPITHELIAL-CADHERIN (E-CADHERIN), RUNT-RELATED TRANSCRIPTION FACTOR 3 (RUNX3), ADENOMATOUS POLYPOSIS COLI (APC), O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT), RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) AND DEATH-ASSOCIATED PROTEIN KINASE (DAPK) HAVE BEEN EXTENSIVELY STUDIED. UNLIKE THE DISTINCT METHYLATION CHARACTERIZATION IN SINGLE GENES, METHYLATION ANALYSIS OF MULTIPLE GENES MAY PROVIDE MORE INFORMATION IN RISK PREDICTION, EARLY DETECTION, PROGNOSIS ASSESSMENT AND CHEMOTHERAPY CHOICE FOR GC. SPECIFICALLY, PARTICULAR MONITORING AND SCREENING SHOULD BE PERFORMED ON THOSE OVER 45 YEARS OLD, WITH PRECANCEROUS GASTRIC DISEASE OR INFECTION OF H. PYLORI OR EBV. AS AN ALTERNATIVE TO TUMOR TISSUES, METHYLATION DETECTION IN PATIENT SERA OR GASTRIC WASHES MAY ALSO BE USED IN RISK PREDICTION AND EARLY DETECTION. HOWEVER, WHAT STILL POSES A GREAT CHALLENGE AS WELL AS A PUZZLE IS THE DETERMINATION OF THE VERY GENES THAT SHOULD BE USED IN METHYLATION ANALYSIS. BECAUSE EPIGENETIC ALTERATIONS ARE NORMALLY REVERSIBLE, DRUGS OR CHEMICAL COMPOUNDS WITH DEMETHYLATING ACTIVITY, SUCH AS 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) COULD BE USED IN THE TREATMENT OF PATIENTS WITH MULTIPLE GENE METHYLATION. IN VIEW OF THE ADVERSE EFFECTS OF 5-AZA-DC, DNMT-TARGETED STRATEGY HAS BEEN PROPOSED AND MAY PROVE TO BE MORE EFFECTIVE THAN DEMETHYLATING AGENTS. 2012 6 2747 39 EXPRESSION ANALYSIS OF THE EPIGENETIC METHYLTRANSFERASES AND METHYL-CPG BINDING PROTEIN FAMILIES IN THE NORMAL B-CELL AND B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CARCINOGENESIS HAS BEEN A SOURCE OF CONTROVERSY FOR SOME TIME. THERE IS LITTLE DOUBT THAT CHANGES IN GENOMIC HYPERMETHYLATION CONTRIBUTE TO THE SILENCING OF TUMOR SUPPRESSOR GENES. FURTHERMORE, RECENT STUDIES HAVE ALSO IDENTIFIED THE SIGNIFICANCE OF GENOMIC HYPOMETHYLATION ASSOCIATED WITH CHROMOSOMAL INSTABILITY AND TUMORIGENESIS. ONE OF THE MOST PERPLEXING QUESTIONS REGARDING EPIGENETIC MODIFICATIONS AND LEUKEMOGENESIS IS THE RELATIONSHIP WITH DNA METHYLTRANSFERASES (DNMT'S). THE PRIMARY FUNCTION OF THE DNMT ENZYMES IS TO METHYLATE GENOMIC DNA, WHEREAS THE METHYL-CPG BINDING DOMAIN PROTEINS (MBD) INTERPRET THIS METHYLATION SIGNAL AND REGULATE GENE EXPRESSION AND CHROMATIN BEHAVIOR. IN THIS STUDY WE ANALYSE THESE GENE FAMILIES BY QUANTITATIVE REAL-TIME PCR TO INVESTIGATE WHETHER EXPRESSION LEVELS AND THE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) PHENOTYPE ARE ASSOCIATED. FURTHERMORE, GIVEN THE EPIGENETIC CROSSTALK BETWEEN GENOME STABILITY AND THE HISTONE CHROMATIN CODE WE HAVE ANALYSED EUKARYOTIC HISTONE METHYLTRANSFERASE (EU-HMTASEI). SURPRISINGLY, WE DID NOT OBSERVE SIGNIFICANT CHANGES IN DNMT1 EXPRESSION IN B-CLL CASES WHEN COMPARED TO NORMAL LYMPHOCYTES, REGARDLESS OF WHETHER WE NORMALISE AGAINST GAPDH OR PCNA AS REFERENCE STANDARDS. INDEED, EXPRESSION OF THE MAINTENANCE AND DE NOVO METHYLASES WERE INDEPENDENTLY REGULATED. OF PARTICULAR NOTE WAS THE SIGNIFICANT DOWN REGULATION OF DNMT3B. FURTHERMORE, WE OBSERVED A POSITIVE CORRELATION BETWEEN HMTASEI EXPRESSION LEVELS AND STAGE OF LEUKEMIA SUGGESTING THAT CHANGES IN THE METHYLATION PATTERNS IN B-CLL MAY REPRESENT DEREGULATION OF THE EPIGENETIC REPERTOIRE THAT ALSO INCLUDE THE METHYLATION DEPENDENT BINDING PROTEINS, MBD2 AND MECP2. WE ENVISAGE CHANGES IN THE EPIGENETIC PROGRAM ARE MULTIFACTORIAL IN NATURE AND POSTULATE THAT THE PREVALENT GENOMIC METHYLASES JUST ONE COMPONENT OF A LARGER EPIGENETIC REPERTOIRE. 2004 7 6661 38 UPREGULATION OF DNA METHYLTRANSFERASE-MEDIATED GENE SILENCING, ANCHORAGE-INDEPENDENT GROWTH, AND MIGRATION OF COLON CANCER CELLS BY INTERLEUKIN-6. INFLAMMATORY BOWEL DISEASE IS CHARACTERIZED BY CHRONIC INFLAMMATION WHICH PREDISPOSES TO COLORECTAL CANCER. THE MECHANISMS BY WHICH INFLAMMATION PROMOTES TUMORIGENESIS ARE NOT FULLY KNOWN. WE AIMED TO INVESTIGATE THE LINKS BETWEEN COLONIC INFLAMMATION AND TUMORIGENESIS VIA EPIGENETIC GENE SILENCING. COLON CANCER SPECIMENS WERE ASSESSED FOR THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT-1) USING IMMUNOHISTOCHEMISTRY. COLORECTAL CARCINOMA CELL LINES WERE ASSESSED FOR DNMT1 EXPRESSION, METHYLCYTOSINE CONTENT, PROMOTER METHYLATION, GENE EXPRESSION, AND TUMORIGENESIS IN RESPONSE TO INTERLEUKIN (IL)-6. DNMT1 WAS EXPRESSED AT HIGHER LEVELS IN BOTH THE PERITUMORAL STROMA AND TUMOR IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED CANCERS COMPARED WITH SPORADIC COLON CANCERS. IL-6 TREATMENT OF COLON CANCER CELLS RESULTED IN AN INCREASE IN DNMT1 EXPRESSION, INDEPENDENT OF DE NOVO GENE EXPRESSION. IL-6 INCREASED THE METHYLATION OF PROMOTER REGIONS OF GENES ASSOCIATED WITH TUMOR SUPPRESSION, ADHESION, AND APOPTOSIS RESISTANCE. EXPRESSION OF A SUBSET OF THESE GENES WAS DOWNREGULATED BY IL-6, AN EFFECT THAT WAS PREVENTED BY PREINCUBATION WITH 5-AZADEOXYCYTIDINE, A DNMT1 INHIBITOR. ANCHORAGE-INDEPENDENT GROWTH AND MIGRATION OF COLON CANCER CELLS WAS ALSO INCREASED BY IL-6 IN A 5-AZADEOXYCYTIDINE-SENSITIVE MANNER. OUR RESULTS INDICATE THAT DNMT-MEDIATED GENE SILENCING MAY PLAY A ROLE IN INFLAMMATION-ASSOCIATED COLON TUMORIGENESIS. 2010 8 4224 35 METHYLATION CHANGES IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE EXPOSED TO ACUTE AND CHRONIC LOW-DOSE X-RAY-IRRADIATION. THE BIOLOGICAL AND GENETIC EFFECTS OF CHRONIC LOW-DOSE RADIATION (LDR) EXPOSURE AND ITS RELATIONSHIP TO CARCINOGENESIS HAVE RECEIVED A LOT OF ATTENTION IN THE RECENT YEARS. FOR EXAMPLE, RADIATION-INDUCED GENOME INSTABILITY, WHICH IS THOUGHT TO BE A PRECURSOR OF TUMOROGENESIS, WAS SHOWN TO HAVE A TRANSGENERATIONAL NATURE. THIS INDICATES A POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LDR-INDUCED GENOME INSTABILITY. GENOMIC DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MECHANISMS. EXISTING DATA ON RADIATION EFFECTS ON DNA METHYLATION PATTERNS IS LIMITED, AND NO ONE HAS SPECIFICALLY STUDIED THE EFFECTS OF THE LDR. WE REPORT THE FIRST STUDY OF THE EFFECTS OF WHOLE-BODY LDR EXPOSURE ON GLOBAL GENOME METHYLATION IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE. IN PARALLEL, WE EVALUATED CHANGES IN PROMOTER METHYLATION AND EXPRESSION OF THE TUMOR SUPPRESSOR GENE P16(INKA) AND DNA REPAIR GENE O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT). WE OBSERVED DIFFERENT PATTERNS OF RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION IN THE LIVER AND MUSCLE OF EXPOSED MALES AND FEMALES. WE ALSO FOUND SEX AND TISSUE-SPECIFIC DIFFERENCES IN P16(INKA) PROMOTER METHYLATION UPON LDR EXPOSURE. IN MALE LIVER TISSUE, P16(INKA) PROMOTER METHYLATION WAS MORE PRONOUNCED THAN IN FEMALE TISSUE. IN CONTRAST, NO SIGNIFICANT RADIATION-INDUCED CHANGES IN P16(INKA) PROMOTER METHYLATION WERE NOTED IN THE MUSCLE TISSUE OF EXPOSED MALES AND FEMALES. RADIATION ALSO DID NOT SIGNIFICANTLY AFFECT METHYLATION STATUS OF MGMT PROMOTER. WE ALSO OBSERVED SUBSTANTIAL SEX DIFFERENCES IN ACUTE AND CHRONIC RADIATION-INDUCED EXPRESSION OF P16(INKA) AND MGMT GENES. ANOTHER IMPORTANT OUTCOME OF OUR STUDY WAS THE FACT THAT CHRONIC LOW-DOSE RADIATION EXPOSURE PROVED TO BE A MORE POTENT INDUCER OF EPIGENETIC EFFECTS THAN THE ACUTE EXPOSURE. THIS SUPPORTS PREVIOUS FINDINGS THAT CHRONIC EXPOSURE LEADS TO GREATER GENOME DESTABILIZATION THAN ACUTE EXPOSURE. 2004 9 3791 41 INTERLEUKIN 6 SUPPORTS THE MAINTENANCE OF P53 TUMOR SUPPRESSOR GENE PROMOTER METHYLATION. A STRONG ASSOCIATION EXISTS BETWEEN STATES OF CHRONIC INFLAMMATION AND CANCER, AND IT IS BELIEVED THAT MEDIATORS OF INFLAMMATION MAY BE RESPONSIBLE FOR THIS PHENOMENON. INTERLEUKIN 6 (IL-6) IS AN INFLAMMATORY CYTOKINE KNOWN TO PLAY A ROLE IN THE GROWTH AND SURVIVAL OF MANY TYPES OF TUMORS, YET THE MECHANISMS EMPLOYED BY THIS PLEOMORPHIC CYTOKINE TO ACCOMPLISH THIS FEAT ARE STILL POORLY UNDERSTOOD. ANOTHER IMPORTANT FACTOR IN TUMOR DEVELOPMENT SEEMS TO BE THE HYPERMETHYLATION OF CPG ISLANDS LOCATED WITHIN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. THIS COMMON EPIGENETIC ALTERATION ENABLES TUMOR CELLS TO REDUCE OR INACTIVATE THE EXPRESSION OF IMPORTANT TUMOR SUPPRESSOR AND CELL CYCLE REGULATORY GENES. HERE WE SHOW THAT IN THE IL-6-RESPONSIVE HUMAN MULTIPLE MYELOMA CELL LINE KAS 6/1, THE PROMOTER REGION OF P53 IS EPIGENETICALLY MODIFIED BY METHYLTRANSFERASES, RESULTING IN DECREASED LEVELS OF EXPRESSION. FURTHERMORE, CELLS TREATED WITH IL-6 EXHIBIT AN INCREASE IN THE EXPRESSION OF THE DNA MAINTENANCE METHYLATION ENZYME, DNMT-1. THE DNA METHYLTRANSFERASE INHIBITOR ZEBULARINE REVERSES THE METHYLATION OF THE P53 PROMOTER, ALLOWING THE RESUMPTION OF ITS EXPRESSION. HOWEVER, WHEN ZEBULARINE IS WITHDRAWN FROM THE CELLS, THE REESTABLISHMENT OF THE ORIGINAL CPG ISLAND METHYLATION WITHIN THE P53 PROMOTER DOES NOT OCCUR IN THE ABSENCE OF IL-6, AND CELLS WHICH DO NOT RECEIVE IL-6 EVENTUALLY DIE, AS P53 EXPRESSION CONTINUES UNCHECKED BY REMETHYLATION. INTERESTINGLY, THIS LOSS OF VIABILITY SEEMS TO INVOLVE NOT THE WITHDRAWAL OF CYTOKINE, BUT THE INABILITY OF THE CELL TO RESILENCE THE PROMOTER. CONSISTENT WITH THIS MODEL, WHEN CELLS THAT EXPRESS IL-6 IN AN AUTOCRINE FASHION ARE SUBJECTED TO IDENTICAL TREATMENT, P53 EXPRESSION IS REDUCED SHORTLY AFTER WITHDRAWAL OF ZEBULARINE. THEREFORE, IT SEEMS IL-6 IS CAPABLE OF MAINTAINING PROMOTER METHYLATION THUS REPRESENTING ONE OF THE POSSIBLE MECHANISMS USED BY INFLAMMATORY MEDIATORS IN THE GROWTH AND SURVIVAL OF TUMORS. 2005 10 6562 34 TRANSIENT AND PERMANENT CHANGES IN DNA METHYLATION PATTERNS IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. CHRONIC LOW DOSE INORGANIC ARSENIC EXPOSURE CAUSES CELLS TO TAKE ON AN EPITHELIAL-TO-MESENCHYMAL PHENOTYPE, WHICH IS A CRUCIAL PROCESS IN CARCINOGENESIS. INORGANIC ARSENIC IS NOT A MUTAGEN AND THUS EPIGENETIC ALTERATIONS HAVE BEEN IMPLICATED IN THIS PROCESS. INDEED, DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, MORPHOLOGIC CHANGES TO CELLS CORRELATE WITH CHANGES IN CHROMATIN STRUCTURE AND GENE EXPRESSION, ULTIMATELY DRIVING THIS PROCESS. HOWEVER, STUDIES ON THE EFFECTS OF INORGANIC ARSENIC EXPOSURE/WITHDRAWAL ON THE EPITHELIAL-TO-MESENCHYMAL TRANSITION AND THE IMPACT OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE LIMITED. IN THIS STUDY WE USED HIGH-RESOLUTION MICROARRAY ANALYSIS TO MEASURE THE CHANGES IN DNA METHYLATION IN CELLS UNDERGOING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND ON THE REVERSAL OF THIS PROCESS, AFTER REMOVAL OF THE INORGANIC ARSENIC EXPOSURE. WE FOUND THAT CELLS EXPOSED TO CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE SHOWED 30,530 SITES WERE DIFFERENTIALLY METHYLATED, AND WITH INORGANIC ARSENIC WITHDRAWAL SEVERAL DIFFERENTIAL METHYLATED SITES WERE REVERSED, ALBEIT NOT COMPLETELY. FURTHERMORE, THESE CHANGES IN DNA METHYLATION MAINLY CORRELATED WITH CHANGES IN GENE EXPRESSION AT MOST SITES TESTED BUT NOT AT ALL. THIS STUDY SUGGESTS THAT DNA METHYLATION CHANGES ON GENE EXPRESSION ARE NOT CLEAR-CUT AND PROVIDE A PLATFORM TO BEGIN TO UNCOVER THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION, SPECIFICALLY WITHIN THE CONTEXT OF INORGANIC ARSENIC TREATMENT. 2017 11 3636 23 INCREASED DNA METHYLTRANSFERASE ACTIVITY AND DNA METHYLATION FOLLOWING EPIDERMAL GROWTH FACTOR STIMULATION IN OVARIAN CANCER CELLS. OVARIAN CANCER PROGRESSION IS CORRELATED WITH ACCUMULATION OF ABERRANT CPG ISLAND METHYLATION. IN OVARIAN CANCER, ASCITES FLUID CONTAINS NUMEROUS EPIDERMAL-GROWTH-FACTOR-RECEPTOR (EGFR) ACTIVATORS, WHICH COULD RESULT IN A TUMOR MICROENVIRONMENT OF CONSTANT EGFR ACTIVATION. SIGNALING PATHWAYS DOWNSTREAM OF EGFR, SUCH AS RAS, REGULATE DNA METHYLATION. WE HYPOTHESIZED THAT CHRONIC EGFR ACTIVATION COULD ALTER DNA METHYLATION. WE FOUND THAT EGFR ACTIVATION INCREASED DNA METHYLTRANSFERASE (DNMT) ACTIVITY ACUTELY, AS WELL AS AFTER LONG-TERM EGF TREATMENT OR EXPRESSION OF A MUTATIONALLY ACTIVATED EGFR. FURTHERMORE, THIS INCREASE IN DNMT ACTIVITY WAS DEPENDENT ON EGFR CATALYTIC ACTIVITY AND RESULTED IN INCREASED GLOBAL DNA METHYLATION. ADDITIONALLY, TREATMENT WITH THE DNMT INHIBITOR/HYPOMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE (AZA) INHIBITED THE EGF INDUCED INCREASE OF BOTH DNMT ACTIVITY AND GLOBAL METHYLATION. THESE DATA SUPPORT A ROLE FOR EGFR IN THE PROCESS OF ACCUMULATED DNA METHYLATION DURING OVARIAN CANCER PROGRESSION AND SUGGEST THAT EPIGENETIC THERAPY MAY BE BENEFICIAL FOR THE TREATMENT OF OVARIAN CANCER. 2012 12 6845 38 [METHYLATION STATUS OF APOPTOSIS GENES AND INTENSITY OF APOPTOTIC DEATH OF PERIPHERAL BLOOD LYMPHOCYTES IN PERSONS CHRONICALLY EXPOSED TO RADIATION]. METHYLATION OF THE CPG ISLANDS OF GENE PROMOTER REGIONS IS THE MOST COMMON EPIGENETIC MODIFICATION INVOLVED IN THE REGULATION OF GENE EXPRESSION. A NUMBER OF STUDIES HAVE SHOWN THAT IONIZING RADIATION CAN CAUSE BOTH HYPER- AND HYPOMETHYLATION OF DNA. ABERRANT METHYLATION AFFECTS CELLULAR PROCESSES AND CAN LEAD TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL STATES. IN THE LITERATURE, THERE ARE FEW STUDIES ON THE METHYLATION STATUS OF HUMAN DNA A LONG TIME AFTER RADIATION EXPOSURE. HERE, THE METHYLATION LEVEL OF CPG ISLANDS OF THE PROMOTER REGIONS OF APOPTOSIS GENES (BCL2, ATM, MDM2, CDKN1A, STAT3, AND NFKB1), AND ALSO ITS INFLUENCE ON APOPTOSIS OF PERIPHERAL BLOOD LYMPHOCYTES IN CHRONICALLY EXPOSED PERSONS WERE STUDIED. RESIDENTS OF THE SOUTH URAL REGION WHO WERE CHRONICALLY EXPOSED TO RADIATION (AFTER DISCHARGES OF RADIOACTIVE WASTES INTO THE TECHA RIVER BY THE "MAYAK PRODUCTION ASSOCIATION" IN 1949-1956) WERE INCLUDED IN THE STUDY. IT WAS ESTABLISHED THAT THE PROPORTION OF INDIVIDUALS WITH HYPERMETHYLATED BCL2 GENE PROMOTER AMONG THE EXPOSED PEOPLE WAS STATISTICALLY SIGNIFICANTLY HIGHER THAN IN THE CONTROL GROUP. THE PERCENTAGE OF METHYLATION OF THE ATM GENE PROMOTER WEAKLY POSITIVELY CORRELATED WITH DOSE AND AGE CHARACTERISTICS. DIFFERENCES IN THE FREQUENCY OF LYMPHOCYTE APOPTOSIS IN EXPOSED INDIVIDUALS WITH A HYPO- OR HYPERMETHYLATED ATM GENE PROMOTER WERE ALSO ESTABLISHED. THE DATA INDICATE THAT, IN THE LONG-TERM, AFTER CHRONIC LOW INTENSITY RADIATION EXPOSURE AT LOW AND MEDIUM DOSES, EPIGENETIC MODIFICATIONS OF THE GENOME OCCUR, WHICH ARE MANIFESTED AS CHANGES IN METHYLATION OF PROMOTER REGIONS OF BCL2 AND ATM GENES. 2022 13 3981 39 LONG-TERM EPIGENETIC THERAPY WITH ORAL ZEBULARINE HAS MINIMAL SIDE EFFECTS AND PREVENTS INTESTINAL TUMORS IN MICE. RECENT SUCCESSES IN THE APPLICATION OF EPIGENETIC DRUGS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME HAVE RAISED QUESTIONS ON THE SAFETY OF LONG-TERM ADMINISTRATION OF DNA METHYLATION INHIBITORS. WE TREATED PREWEANED CANCER PRONE APC(MIN/+) (MIN) MICE CONTINUOUSLY WITH THE DNA METHYLATION INHIBITOR ZEBULARINE IN THEIR DRINKING WATER TO DETERMINE THE EFFECTS OF THE DRUG ON NORMAL MOUSE DEVELOPMENT AS WELL AS CANCER PREVENTION. ZEBULARINE CAUSED A TISSUE-SPECIFIC REDUCTION IN DNA METHYLATION AT B1 SHORT INTERSPERSED NUCLEOTIDE ELEMENTS IN THE SMALL AND LARGE INTESTINES OF FEMALE MIN MICE BUT NOT IN OTHER ORGANS EXAMINED AFTER CHRONIC ORAL TREATMENT. NO SIGNIFICANT DIFFERENCE IN THE AVERAGE WEIGHTS OF MICE WAS OBSERVED DURING THE TREATMENT. IN ADDITION, ANALYSIS OF GLOBAL GENE EXPRESSION OF COLONIC EPITHELIAL CELLS FROM THE FEMALES INDICATED THAT ONLY 3% TO 6% OF THE GENES WERE AFFECTED IN THEIR EXPRESSION. WE DID NOT DETECT TOXICITY AND ABNORMALITIES FROM THE HISTOPATHOLOGIC ANALYSIS OF LIVER AND INTESTINAL TISSUES. LASTLY, WE TESTED WHETHER PREVENTION OF TUMORIGENESIS CAN BE ACHIEVED WITH CHRONIC ORAL ADMINISTRATION OF ZEBULARINE IN MIN MICE. THE AVERAGE NUMBER OF POLYPS IN MIN FEMALES DECREASED FROM 58 TO 1, WHEREAS THE AVERAGE POLYP NUMBER REMAINED UNAFFECTED IN MIN MALES POSSIBLY DUE TO DIFFERENTIAL ACTIVITY OF ALDEHYDE OXIDASE. TAKEN TOGETHER, OUR RESULTS SHOW FOR THE FIRST TIME THAT LONG-TERM ORAL ADMINISTRATION OF ZEBULARINE CAUSES A GENDER-SPECIFIC ABROGATION OF INTESTINAL TUMORS WHILE CAUSING A TISSUE-SPECIFIC DNA DEMETHYLATION. IMPORTANTLY, PROLONGED TREATMENT OF MICE WITH EPIGENETIC DRUGS RESULTED IN ONLY MINOR DEVELOPMENTAL AND HISTOLOGIC CHANGES. 2008 14 59 36 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS. 2010 15 416 42 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION. 2019 16 476 51 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 17 1655 25 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 18 342 30 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 19 3686 26 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES. 2009 20 2297 27 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014