1 2880 160 FUSOBACTERIUM NUCLEATUM INFECTION IN COLORECTAL CANCER: LINKING INFLAMMATION, DNA MISMATCH REPAIR AND GENETIC AND EPIGENETIC ALTERATIONS. IT HAS BEEN RECENTLY REPORTED THAT THE POPULATION OF FUSOBACTERIUM, PARTICULARLY FUSOBACTERIUM NUCLEATUM (FN), IS OVERREPRESENTED IN COLORECTAL CANCERS AND ADENOMAS. THE PROMOTING EFFECTS OF FN INFECTION ON ADENOMA AND/OR CARCINOMA FORMATION HAVE BEEN SHOWN IN APC(MIN/+)MICE. CHARACTERISTICS OF FN-ASSOCIATED CRC WERE IDENTIFIED THROUGH STUDIES USING HUMAN CRC COHORTS, AND INCLUDE RIGHT-SIDED COLON LOCATION, CPG ISLAND METHYLATION PHENOTYPE-HIGH (CIMP-H), HIGH LEVEL OF MICROSATELLITE INSTABILITY (MSI-H), AND POOR PATIENT PROGNOSIS. A SUBSET OF FN-ASSOCIATED CRC EXHIBITS A LOW LEVEL OF MICROSATELLITE INSTABILITY (MSI-L) AND ELEVATED MICROSATELLITE ALTERATIONS IN SELECTED TETRA-NUCLEOTIDE REPEATS (EMAST) INDUCED BY TRANSLOCATION OF MSH3 FROM THE NUCLEUS TO THE CYTOPLASM IN RESPONSE TO OXIDATIVE DNA DAMAGE OR INFLAMMATORY SIGNALS. THE ASSOCIATION BETWEEN CIMP/MSI-H AND FN-INFECTION CAN BE EXPLAINED BY THE ROLE OF THE MISMATCH REPAIR (MMR) PROTEIN COMPLEX FORMED BETWEEN MSH2 AND MSH6 (MUTSALPHA) TO REPAIR ABERRANT BASES GENERATED BY ROS TO FORM 7,8-DIHYDRO-8-OXO-GUANINE (8-OXOG). CLUSTERED 8-OXOGS FORMED AT CPG-RICH REGIONS INCLUDING PROMOTERS BY ROS IS REFRACTORY TO BASE EXCISION REPAIR (BER). UNDER THESE CONDITIONS, MUTSALPHA INITIATES REPAIR IN COOPERATION WITH DNA METHYLTRANSFERASES (DNMTS) AND THE POLYCOMB REPRESSIVE COMPLEX 4 (PRC4). DNMTS AT DAMAGED SITES METHYLATE CPG ISLANDS TO REPRESS TRANSCRIPTION OF TARGET GENES AND PROMOTE REPAIR REACTIONS. THUS, CONTINUOUS GENERATION OF ROS THROUGH CHRONIC FN INFECTION MAY INITIATE 1) CIMP-POSITIVE ADENOMA AND CARCINOMA IN AN MSH2/MSH6-DEPENDENT MANNER, AND/OR 2) MSI-L/EMAST CRC IN AN MSH3-DEPENDENT MANNER. THE POOR PROGNOSIS OF FN-ASSOCIATED CRC CAN BE EXPLAINED BY FN-INDUCED IMMUNE-EVASION AND/OR CHEMO-RESISTANCE. 2018 2 3804 26 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 3 3865 48 JAK2 REGULATES MISMATCH REPAIR PROTEIN-MEDIATED EPIGENETIC ALTERATIONS IN RESPONSE TO OXIDATIVE DAMAGE. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS UNDERGO ABERRANT DNA METHYLATION THAT CONTRIBUTES TO TUMORIGENESIS. INFLAMMATION IS ASSOCIATED WITH AN INCREASE IN REACTIVE OXYGEN SPECIES (ROS) THAT CAUSE OXIDATIVE DNA DAMAGE, WHICH HAS ALSO BEEN LINKED TO EPIGENETIC ALTERATIONS. WE PREVIOUSLY DEMONSTRATED THAT IN RESPONSE TO ROS, MISMATCH REPAIR PROTEINS MSH2 AND MSH6 RECRUIT EPIGENETIC SILENCING PROTEINS DNA METHYLTRANSFERASE 1 (DNMT1) AND POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) MEMBERS TO SITES OF DNA DAMAGE, RESULTING IN TRANSCRIPTIONAL REPRESSION OF TUMOR SUPPRESSOR GENES (TSGS). HOWEVER, IT WAS UNCLEAR WHAT SIGNAL IS UNIQUE TO ROS THAT RESULTS IN THE CHROMATIN BINDING OF MSH2 AND MSH6. HEREIN, WE DEMONSTRATE THAT IN RESPONSE TO HYDROGEN PEROXIDE (H(2) O(2) ), JAK2 LOCALIZES TO THE NUCLEUS AND INTERACTS WITH MSH2 AND MSH6. INHIBITION OR KNOCKDOWN OF JAK2 REDUCES THE H(2) O(2) -INDUCED CHROMATIN INTERACTION OF MSH2, MSH6, DNMT1, AND PRC2 MEMBERS, REDUCES H(2) O(2) -INDUCED GLOBAL INCREASE IN TRIMETHYLATION OF LYSINE 27 OF HISTONE H3 (H3K27ME3), AND ABROGATES OXIDATIVE DAMAGE-INDUCED TRANSCRIPTIONAL REPRESSION OF CANDIDATE TSGS. MOREOVER, JAK2 MRNA EXPRESSION IS ASSOCIATED WITH CPG ISLAND METHYLATOR PHENOTYPE (CIMP) STATUS IN HUMAN COLORECTAL CANCER. OUR FINDINGS PROVIDE NOVEL INSIGHT INTO THE CONNECTION BETWEEN KINASE ACTIVATION AND EPIGENETIC ALTERATIONS DURING OXIDATIVE DAMAGE AND INFLAMMATION. ENVIRON. MOL. MUTAGEN. 60:308-319, 2019. (C) 2018 WILEY PERIODICALS, INC. 2019 4 2843 42 FREQUENT CPG ISLAND METHYLATION IN PRECURSOR LESIONS AND EARLY GASTRIC ADENOCARCINOMAS. GASTRIC CARCINOGENESIS INVOLVES MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC SILENCING OF TUMOR-RELATED GENES DUE TO CPG ISLAND METHYLATION (CIM) HAS BEEN RECENTLY REPORTED IN GASTRIC CANCER, BUT THE ROLE IN PRECURSOR LESIONS IS NOT WELL UNDERSTOOD. WE ANALYSED THE METHYLATION STATUS OF THE TUMOR SUPPRESSOR GENE P16, THE DNA MISMATCH REPAIR GENE HMLH1, AND FOUR CPG ISLANDS (MINT1, MINT2, MINT25, AND MINT31) USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION IN 35 POLYPOID ADENOMAS AND 46 FLAT DYSPLASIAS UNASSOCIATED WITH CARCINOMA, 34 EARLY ADENOCARCINOMAS (T1N0M0) AND ASSOCIATED ADENOMAS/DYSPLASIAS, AND CORRESPONDING ADJACENT NON-NEOPLASTIC MUCOSA. THE EXTENT OF CIM WAS DEFINED BY THE FRACTION OF METHYLATED LOCI (METHYLATION INDEX), AND COMPARED WITH PREVIOUSLY CHARACTERIZED GENETIC ALTERATIONS (MICROSATELLITE INSTABILITY (MSI) AND APC GENE MUTATION). WE FOUND THAT METHYLATION OF P16 WAS MORE FREQUENT IN ADENOCARCINOMA-ASSOCIATED DYSPLASIAS/ADENOMAS (29%) AND ADENOCARCINOMAS (44%) AS COMPARED TO FLAT DYSPLASIAS (4%) AND ADENOMAS (18%) UNASSOCIATED WITH ADENOCARCINOMA (P=0.001). THE MEAN METHYLATION INDEX INCREASED FROM NORMAL/CHRONIC GASTRITIS (CG) MUCOSA (0.09) TO INTESTINAL METAPLASIA (IM) (0.16), FLAT DYSPLASIAS (0.40) OR POLYPOID ADENOMAS (0.41) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH CARCINOMA (0.44), AND ADENOCARCINOMAS (0.44). THERE WAS NO DIFFERENCE IN FREQUENCIES OF HIGH-LEVEL CPG ISLAND METHYLATION (CIM-H, METHYLATION INDEX > OR =0.5) AMONG FLAT DYSPLASIAS (50%) AND POLYPOID ADENOMAS (51%) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH ADENOCARCINOMA (47%), AND ADENOCARCINOMA (47%). CIM-H WAS PRESENT IN 15% OF IM, BUT NOT IN NORMAL/CG MUCOSA. THERE WAS A SIGNIFICANT CORRELATION BETWEEN METHYLATION OF HMLH1 AND HIGH-LEVEL OF MICROSATELLITE INSTABILITY (MSI-H): METHYLATION OF HMLH1 WAS PRESENT IN 71% OF MSI-H TUMORS, BUT ONLY 8% OF MSI-LOW TUMORS AND 13% OF MICROSATELLITE-STABLE TUMORS (P=0.0001). THERE WAS NO STATISTICAL DIFFERENCE BETWEEN METHYLATION INDEX AND APC MUTATION. OUR RESULTS INDICATE THAT CONCURRENT PROMOTER METHYLATION IS AN EARLY AND FREQUENT EVENT IN GASTRIC TUMORIGENESIS, INCLUDING BOTH MSI-H AND MICROSATELLITE-STABLE NEOPLASMS. METHYLATION OF THE P16 GENE MAY CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF GASTRIC PRECURSOR LESIONS. 2004 5 499 42 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 6 6579 24 TREFOIL FACTORS AND HUMAN GASTRIC CANCER (REVIEW). TFF1/PS2, TFF2/SP AND TFF3/ITF ARE SOLUBLE PEPTIDES WITH TREFOIL DOMAIN(S) AND C-TERMINAL DIMERIZATION DOMAIN, WHICH ARE CONSERVED AMONG HUMAN, COW, MOUSE AND RAT. TFF1 MRNA IS EXPRESSED IN STOMACH (MUCOUS CELLS IN FUNDUS AND ANTRUM), TFF2 MRNA IN STOMACH (MUCOUS NECK CELLS IN FUNDUS AND BASAL CELLS IN ANTRAL AND PYLORIC GLANDS) AND DUODENUM (BRUNNER'S GLAND), TFF3 MRNA IN SMALL INTESTINE AND LARGE INTESTINE (GOBLET CELLS). EXPRESSION OF TFF1, TFF2 AND TFF3 MRNAS ARE DIFFERENTIALLY REGULATED BY FGF2/BFGF, FGF7/KGF, ESTROGEN, ASPIRIN, ARACHIDONIC ACID, X-RAY IRRADIATION, AND HYDROGEN PEROXIDE. GASTRIC CANCER IS CLASSIFIED INTO THE INTESTINAL TYPE AND THE DIFFUSE TYPE. TFF MRNAS ARE PREFERENTIALLY EXPRESSED IN DIFFUSE-TYPE GASTRIC CANCER CELLS. CUSTOM-MADE MICROARRAY (TFF MRNAS) AND ELISA (TFF PROTEINS) MIGHT BE APPLICABLE FOR SCREENING METHODS OF PERITONEAL AND BONE MARROW DISSEMINATION FROM DIFFUSE-TYPE GASTRIC CANCER. TFF1 AND TFF2 MRNAS ARE FREQUENTLY DOWN-REGULATED IN INTESTINAL-TYPE GASTRIC CANCER. TFF1 GENE, INACTIVATED BY DELETION, MISSENSE MUTATION AND PROMOTER HYPERMETHYLATION, IS A TUMOR SUPPRESSOR GENE IMPLICATED IN GASTRIC CANCER. TFF2 IS A CANDIDATE TUMOR SUPPRESSOR GENE; HOWEVER, GENETIC AND EPIGENETIC ALTERATIONS OF TFF2 GENE IN HUMAN GASTRIC CANCER REMAIN UNCLEAR. TFF1, TFF2 AND TFF3 PLAY KEY ROLES IN MUCOSAL PROTECTION THROUGH MUCOUS-BARRIER FORMATION, AND ALSO IN MUCOSAL REPAIR THROUGH PROMOTION OF RESTITUTION AFTER INJURY. PATIENTS WITH CHRONIC ATROPHIC GASTRITIS AND THOSE WITH ULCERATIVE COLITIS ARE AT RISK OF GASTRIC CANCER AND COLORECTAL CANCER, RESPECTIVELY. TFF1, TFF2 AND TFF3 PROTEINS MIGHT BE APPLICABLE FOR CHEMOPREVENTION OF GASTROINTESTINAL CANCER ASSOCIATED WITH CHRONIC PERSISTENT INFLAMMATION. 2003 7 4374 49 MISMATCH REPAIR PROTEINS RECRUIT DNA METHYLTRANSFERASE 1 TO SITES OF OXIDATIVE DNA DAMAGE. AT SITES OF CHRONIC INFLAMMATION, EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES AND UNDERGO CANCER-ASSOCIATED DNA METHYLATION CHANGES, SUGGESTING THAT INFLAMMATION MAY INITIATE EPIGENETIC ALTERATIONS. PREVIOUSLY, WE DEMONSTRATED THAT OXIDATIVE DAMAGE CAUSES EPIGENETIC SILENCING PROTEINS TO BECOME PART OF A LARGE COMPLEX THAT IS LOCALIZED TO GC-RICH REGIONS OF THE GENOME, INCLUDING PROMOTER CPG ISLANDS THAT ARE EPIGENETICALLY SILENCED IN CANCER. HOWEVER, WHETHER THESE PROTEINS WERE RECRUITED DIRECTLY TO DAMAGED DNA OR DURING THE DNA REPAIR PROCESS WAS UNKNOWN. HERE WE DEMONSTRATE THAT THE MISMATCH REPAIR PROTEIN HETERODIMER MSH2-MSH6 PARTICIPATES IN THE OXIDATIVE DAMAGE-INDUCED RECRUITMENT OF DNA METHYLTRANSFERASE 1 (DNMT1) TO CHROMATIN. HYDROGEN PEROXIDE TREATMENT INDUCES THE INTERACTION OF MSH2-MSH6 WITH DNMT1, SUGGESTING THAT THE RECRUITMENT IS THROUGH A PROTEIN-PROTEIN INTERACTION. IMPORTANTLY, THE REDUCTION IN TRANSCRIPTION FOR GENES WITH CPG ISLAND-CONTAINING PROMOTERS CAUSED BY OXIDATIVE DAMAGE IS ABROGATED BY KNOCKDOWN OF MSH6 AND/OR DNMT1. OUR FINDINGS PROVIDE EVIDENCE THAT THE ROLE OF DNMT1 AT SITES OF OXIDATIVE DAMAGE IS TO REDUCE TRANSCRIPTION, POTENTIALLY PREVENTING TRANSCRIPTION FROM INTERFERING WITH THE REPAIR PROCESS. THIS STUDY UNIQUELY BRINGS TOGETHER SEVERAL FACTORS THAT ARE KNOWN TO CONTRIBUTE TO COLON CANCER, NAMELY INFLAMMATION, MISMATCH REPAIR PROTEINS, AND EPIGENETIC CHANGES. 2016 8 2391 34 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 9 6671 24 UROPATHOGENIC ESCHERICHIA COLI INFECTION-INDUCED EPITHELIAL TRAINED IMMUNITY IMPACTS URINARY TRACT DISEASE OUTCOME. PREVIOUS URINARY TRACT INFECTIONS (UTIS) CAN PREDISPOSE ONE TO FUTURE INFECTIONS; HOWEVER, THE UNDERLYING MECHANISMS AFFECTING RECURRENCE ARE POORLY UNDERSTOOD. WE PREVIOUSLY FOUND THAT UTIS IN MICE CAUSE DIFFERENTIAL BLADDER EPITHELIAL (UROTHELIAL) REMODELLING, DEPENDING ON DISEASE OUTCOME, THAT IMPACTS SUSCEPTIBILITY TO RECURRENT UTI. HERE WE COMPARED UROTHELIAL STEM CELL (USC) LINES ISOLATED FROM MICE WITH A HISTORY OF EITHER RESOLVED OR CHRONIC UROPATHOGENIC ESCHERICHIA COLI (UPEC) INFECTION, ELUCIDATING EVIDENCE OF MOLECULAR IMPRINTING THAT INVOLVED EPIGENETIC CHANGES, INCLUDING DIFFERENCES IN CHROMATIN ACCESSIBILITY, DNA METHYLATION AND HISTONE MODIFICATION. EPIGENETIC MARKS IN USCS FROM CHRONICALLY INFECTED MICE ENHANCED CASPASE-1-MEDIATED CELL DEATH UPON UPEC INFECTION, PROMOTING BACTERIAL CLEARANCE. INCREASED PTGS2OS2 EXPRESSION ALSO OCCURRED, POTENTIALLY CONTRIBUTING TO SUSTAINED CYCLOOXYGENASE-2 EXPRESSION, BLADDER INFLAMMATION AND MUCOSAL WOUNDING-RESPONSES ASSOCIATED WITH SEVERE RECURRENT CYSTITIS. THUS, UPEC INFECTION ACTS AS AN EPI-MUTAGEN REPROGRAMMING THE UROTHELIAL EPIGENOME, LEADING TO UROTHELIAL-INTRINSIC REMODELLING AND TRAINING OF THE INNATE RESPONSE TO SUBSEQUENT INFECTION. 2023 10 714 31 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 11 4409 31 MOLECULAR ANATOMY AND PATHOGENIC ACTIONS OF HELICOBACTER PYLORI CAGA THAT UNDERPIN GASTRIC CARCINOGENESIS. CHRONIC INFECTION WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS IS THE STRONGEST RISK FACTOR FOR GASTRIC CANCER. THE CAGA GENE PRODUCT, CAGA, IS DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE BACTERIAL TYPE IV SECRETION SYSTEM. DELIVERED CAGA THEN UNDERGOES TYROSINE PHOSPHORYLATION AT THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS IN ITS C-TERMINAL REGION AND ACTS AS AN ONCOGENIC SCAFFOLD PROTEIN THAT PHYSICALLY INTERACTS WITH MULTIPLE HOST SIGNALING PROTEINS IN BOTH TYROSINE PHOSPHORYLATION-DEPENDENT AND -INDEPENDENT MANNERS. ANALYSIS OF CAGA USING IN VITRO CULTURED GASTRIC EPITHELIAL CELLS HAS INDICATED THAT THE NONPHYSIOLOGICAL SCAFFOLDING ACTIONS OF CAGA CELL-AUTONOMOUSLY PROMOTE THE MALIGNANT TRANSFORMATION OF THE CELLS BY ENDOWING THE CELLS WITH MULTIPLE PHENOTYPIC CANCER HALLMARKS: SUSTAINED PROLIFERATION, EVASION OF GROWTH SUPPRESSORS, INVASIVENESS, RESISTANCE TO CELL DEATH, AND GENOMIC INSTABILITY. TRANSGENIC EXPRESSION OF CAGA IN MICE LEADS TO IN VIVO ONCOGENIC ACTION OF CAGA WITHOUT ANY OVERT INFLAMMATION. THE IN VIVO ONCOGENIC ACTIVITY OF CAGA IS FURTHER POTENTIATED IN THE PRESENCE OF CHRONIC INFLAMMATION. SINCE HELICOBACTER PYLORI INFECTION TRIGGERS A PROINFLAMMATORY RESPONSE IN HOST CELLS, A FEEDFORWARD STIMULATION LOOP THAT AUGMENTS THE ONCOGENIC ACTIONS OF CAGA AND INFLAMMATION IS CREATED IN CAGA-INJECTED GASTRIC MUCOSA. GIVEN THAT HELICOBACTER PYLORI IS NO LONGER COLONIZED IN ESTABLISHED GASTRIC CANCER LESIONS, THE MULTISTEP NATURE OF GASTRIC CANCER DEVELOPMENT SHOULD INCLUDE A "HIT-AND-RUN" PROCESS OF CAGA ACTION. THUS, ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS THAT COMPENSATE FOR CAGA-DIRECTED CANCER HALLMARKS MAY BE REQUIRED FOR COMPLETION OF THE "HIT-AND-RUN" PROCESS OF GASTRIC CARCINOGENESIS. 2020 12 5582 40 ROLE OF NITRATIVE AND OXIDATIVE DNA DAMAGE IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION INDUCED BY BIOLOGICAL, CHEMICAL, AND PHYSICAL FACTORS HAS BEEN FOUND TO BE ASSOCIATED WITH THE INCREASED RISK OF CANCER IN VARIOUS ORGANS. WE REVEALED THAT INFECTIOUS AGENTS INCLUDING LIVER FLUKE, HELICOBACTER PYLORI, AND HUMAN PAPILLOMA VIRUS AND NONINFECTIOUS AGENTS SUCH AS ASBESTOS FIBER INDUCED INOS-DEPENDENT FORMATION OF 8-NITROGUANINE AND 8-OXO-7, 8-DIHYDRO-2'-DEOXYGUANOSINE (8-OXODG) IN CANCER TISSUES AND PRECANCEROUS REGIONS. OUR RESULTS WITH THE COLOCALIZATION OF PHOSPHORYLATED ATM AND GAMMA-H2AX WITH 8-OXODG AND 8-NITROGUANINE IN INFLAMMATION-RELATED CANCER TISSUES SUGGEST THAT DNA BASE DAMAGE LEADS TO DOUBLE-STRANDED BREAKS. IT IS INTERESTING FROM THE ASPECT OF GENETIC INSTABILITY. WE ALSO DEMONSTRATED IL-6-MODULATED INOS EXPRESSION VIA STAT3 AND EGFR IN EPSTEIN-BARR-VIRUS-ASSOCIATED NASOPHARYNGEAL CARCINOMA AND FOUND PROMOTER HYPERMETHYLATION IN SEVERAL TUMOR SUPPRESSOR GENES. SUCH EPIGENETIC ALTERATION MAY OCCUR BY CONTROLLING THE DNA METHYLATION THROUGH IL-6-MEDIATED JAK/STAT3 PATHWAYS. COLLECTIVELY, 8-NITROGUANINE WOULD BE A USEFUL BIOMARKER FOR PREDICTING THE RISK OF INFLAMMATION-RELATED CANCERS. 2012 13 979 31 CHRONIC OXIDATIVE STRESS INCREASES RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY IN RENAL CARCINOMA CELLS POTENTIALLY THROUGH EPIGENETIC MECHANISM. RENAL CELL CARCINOMA IS THE MOST COMMON FORM OF KIDNEY CANCER AND IS HIGHLY RESISTANT TO CHEMOTHERAPY. ALTHOUGH THE ROLE OF OXIDATIVE STRESS IN KIDNEY CANCER IS KNOWN, THE CHEMOTHERAPEUTIC RESPONSE OF CANCER CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS IS NOT CLEAR. HENCE, THE EFFECT OF OXIDATIVE STRESS ON SENSITIVITY TO DOXORUBICIN-INDUCED CYTOTOXICITY WAS EVALUATED USING AN IN VITRO MODEL OF HUMAN KIDNEY CANCER CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. RESULTS OF MTT- AND ANCHORAGE-INDEPENDENT GROWTH ASSAYS AND CELL CYCLE ANALYSIS REVEALED SIGNIFICANT DECREASE IN SENSITIVITY TO DOXORUBICIN IN CAKI-1 CELLS ADAPTED TO OXIDATIVE STRESS. CHANGES IN THE EXPRESSION OF GENES INVOLVED IN DRUG TRANSPORT, CELL SURVIVAL, AND DNA REPAIR-DEPENDENT APOPTOSIS FURTHER CONFIRMED INCREASED RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY IN THESE CELLS. DECREASED EXPRESSION OF MISMATCH REPAIR (MMR) GENE MSH2 IN CELLS EXPOSED TO OXIDATIVE STRESS SUGGESTS THAT LOSS OF MMR-DEPENDENT APOPTOSIS COULD BE A POTENTIAL MECHANISM FOR INCREASED RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY. ADDITIONALLY, DOWNREGULATION OF HDAC1, AN INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION, AND HYPERMETHYLATION OF MSH2 PROMOTER WERE ALSO OBSERVED IN CAKI-1 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. DNA-DEMETHYLATING AGENT 5-AZA-2DC SIGNIFICANTLY RESTORED THE EXPRESSION OF MSH2 AND DOXORUBICIN-INDUCED CYTOTOXICITY IN CAKI-1 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS, SUGGESTING THE ROLE OF DNA HYPERMETHYLATION IN INACTIVATION OF MSH2 EXPRESSION AND CONSEQUENTLY MMR-DEPENDENT APOPTOSIS IN THESE CELLS. IN SUMMARY, THIS STUDY FOR THE FIRST TIME PROVIDES DIRECT EVIDENCE FOR THE ROLE OF OXIDATIVE STRESS IN CHEMOTHERAPEUTIC RESISTANCE IN RENAL CARCINOMA CELLS POTENTIALLY THROUGH EPIGENETIC MECHANISM. 2016 14 6871 22 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 15 3666 30 INFECTION, STEM CELLS AND CANCER SIGNALS. THE ASSOCIATION OF CANCER WITH PRECEDING PARASITIC INFECTIONS HAS BEEN OBSERVED FOR OVER 200 YEARS. SOME SUCH CANCERS ARISE FROM INFECTION OF TISSUE STEM CELLS BY VIRUSES WITH INSERTION OF VIRAL ONCOGENES INTO THE HOST DNA (MOUSE POLYOMA VIRUS, MOUSE MAMMARY TUMOR VIRUS). IN OTHER CASES THE VIRUS DOES NOT INSERT ITS DNA INTO THE HOST CELLS, BUT RATHER COMMANDEERS THE METABOLISM OF THE INFECTED CELLS, SO THAT THE CELLS CONTINUE TO PROLIFERATE AND DO NOT DIFFERENTIATE (HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER). CYTOPLASMIC EPSTEIN BARR VIRUS INFECTION IS ASSOCIATED WITH A SPECIFIC GENE TRANSLOCATION (IG/C-MYC) THAT ACTIVATES PROLIFERATION OF AFFECTED CELLS (BURKITT LYMPHOMA). IN CHRONIC OSTEOMYELITIS AN INFLAMMATORY REACTION TO THE INFECTION APPEARS TO ACT THROUGH PRODUCTION OF INFLAMMATORY CYTOKINES AND OXYGEN RADICAL FORMATION TO INDUCE EPITHELIAL CANCERS. INFECTION WITH HELICOBACTER PYLORI LEADS TO EPIGENETIC CHANGES IN METHYLATION AND INFECTION BY A PARASITE. CLONORCHIS SINENSIS ALSO ACTS AS A PROMOTER OF CANCER OF THE BILE DUCTS OF THE LIVER (CHOLANIOCARCINOMA). THE COMMON THREAD AMONG THESE DIVERSE PATHWAYS IS THAT THE INFECTIONS ACT TO ALTER TISSUE STEM CELL SIGNALING WITH CONTINUED PROLIFERATION OF TUMOR TRANSIT AMPLIFYING CELLS. 2011 16 4984 26 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 17 24 30 8-OXOGUANINE DNA GLYCOSYLASE-1-DRIVEN DNA BASE EXCISION REPAIR: ROLE IN ASTHMA PATHOGENESIS. PURPOSE OF REVIEW: TO PROVIDE BOTH AN OVERVIEW AND EVIDENCE OF THE POTENTIAL CAUSE OF OXIDATIVE DNA BASE DAMAGE AND REPAIR SIGNALING IN CHRONIC INFLAMMATION AND HISTOLOGICAL CHANGES ASSOCIATED WITH ASTHMA. RECENT FINDINGS: ASTHMA IS INITIATED/MAINTAINED BY IMMUNOLOGICAL, GENETIC/EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS A WORLD-WIDE HEALTH PROBLEM, AS CURRENT THERAPIES SUPPRESS SYMPTOMS RATHER THAN PREVENT/REVERSE THE DISEASE, LARGELY DUE TO GAPS IN UNDERSTANDING ITS MOLECULAR MECHANISMS. INFLAMMATION, OXIDATIVE STRESS, AND DNA DAMAGE ARE INSEPARABLE PHENOMENA, BUT THEIR MOLECULAR ROLES IN ASTHMA PATHOGENESIS ARE UNCLEAR. IT WAS FOUND THAT AMONG OXIDATIVELY MODIFIED DNA BASES, 8-OXOGUANINE (8-OXOG) IS ONE OF THE MOST ABUNDANT, AND ITS LEVELS IN DNA AND BODY FLUIDS ARE CONSIDERED A BIOMARKER OF ONGOING ASTHMATIC PROCESSES. FREE 8-OXOG FORMS A COMPLEX WITH 8-OXOG DNA GLYCOSYLASE-1 AND ACTIVATES RAS-FAMILY GTPASES THAT INDUCE GENE EXPRESSION TO MOBILIZE INNATE AND ADAPTIVE IMMUNE SYSTEMS, ALONG WITH GENES REGULATING AIRWAY HYPERPLASIA, HYPER-RESPONSIVENESS, AND LUNG REMODELING IN ATOPIC AND NONATOPIC ASTHMA. SUMMARY: DNA'S INTEGRITY MUST BE MAINTAINED TO PREVENT MUTATION, SO ITS CONTINUOUS REPAIR AND DOWNSTREAM SIGNALING 'FUEL' CHRONIC INFLAMMATORY PROCESSES IN ASTHMA AND FORM THE BASIC MECHANISM WHOSE ELUCIDATION WILL ALLOW THE DEVELOPMENT OF NEW DRUG TARGETS FOR THE PREVENTION/REVERSAL OF LUNG DISEASES. 2015 18 3232 21 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 19 2867 29 FUNCTIONAL AND CANCER GENOMICS OF ASXL FAMILY MEMBERS. ADDITIONAL SEX COMBS-LIKE (ASXL)1, ASXL2 AND ASXL3 ARE HUMAN HOMOLOGUES OF THE DROSOPHILA ASX GENE THAT ARE INVOLVED IN THE REGULATION OR RECRUITMENT OF THE POLYCOMB-GROUP REPRESSOR COMPLEX (PRC) AND TRITHORAX-GROUP (TRXG) ACTIVATOR COMPLEX. ASXL PROTEINS CONSIST OF ASXN, ASXH, ASXM1, ASXM2 AND PHD DOMAINS. ASXL1 DIRECTLY INTERACTS WITH BAP1, KDM1A (LSD1), NCOA1 AND NUCLEAR HORMONE RECEPTORS (NHRS), SUCH AS RETINOIC ACID RECEPTORS, OESTROGEN RECEPTOR AND ANDROGEN RECEPTOR. ASXL FAMILY MEMBERS ARE EPIGENETIC SCAFFOLDING PROTEINS THAT ASSEMBLE EPIGENETIC REGULATORS AND TRANSCRIPTION FACTORS TO SPECIFIC GENOMIC LOCI WITH HISTONE MODIFICATIONS. ASXL1 IS INVOLVED IN TRANSCRIPTIONAL REPRESSION THROUGH AN INTERACTION WITH PRC2 AND ALSO CONTRIBUTES TO TRANSCRIPTIONAL REGULATION THROUGH INTERACTIONS WITH BAP1 AND/OR NHR COMPLEXES. GERM-LINE MUTATIONS OF HUMAN ASXL1 AND ASXL3 OCCUR IN BOHRING-OPITZ AND RELATED SYNDROMES. AMPLIFICATION AND OVEREXPRESSION OF ASXL1 OCCUR IN CERVICAL CANCER. TRUNCATION MUTATIONS OF ASXL1 OCCUR IN COLORECTAL CANCERS WITH MICROSATELLITE INSTABILITY (MSI), MALIGNANT MYELOID DISEASES, CHRONIC LYMPHOCYTIC LEUKAEMIA, HEAD AND NECK SQUAMOUS CELL CARCINOMA, AND LIVER, PROSTATE AND BREAST CANCERS; THOSE OF ASXL2 OCCUR IN PROSTATE CANCER, PANCREATIC CANCER AND BREAST CANCER AND THOSE OF ASXL3 ARE OBSERVED IN MELANOMA. EPC1-ASXL2 GENE FUSION OCCURS IN ADULT T-CELL LEUKAEMIA/LYMPHOMA. THE PROGNOSIS OF MYELOID MALIGNANCIES WITH MISREGULATING TRUNCATION MUTATIONS OF ASXL1 IS POOR. ASXL FAMILY MEMBERS ARE ASSUMED TO BE TUMOUR SUPPRESSIVE OR ONCOGENIC IN A CONTEXT-DEPENDENT MANNER. 2013 20 5064 34 PHOSPHORYLATION OF RELA/P65 PROMOTES DNMT-1 RECRUITMENT TO CHROMATIN AND REPRESSES TRANSCRIPTION OF THE TUMOR METASTASIS SUPPRESSOR GENE BRMS1. THE MAJORITY OF PATIENTS WITH LUNG CANCER PRESENT WITH METASTATIC DISEASE. CHRONIC INFLAMMATION AND SUBSEQUENT ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) HAVE BEEN ASSOCIATED WITH THE DEVELOPMENT OF CANCERS. THE RELA/P65 SUBUNIT OF NF-KAPPAB IS TYPICALLY ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. IN THIS REPORT WE SHOW THAT RELA/P65 CAN FUNCTION AS AN ACTIVE TRANSCRIPTIONAL REPRESSOR THROUGH ENHANCED METHYLATION OF THE BRMS1 (BREAST CANCER METASTASIS SUPPRESSOR 1) METASTASIS SUPPRESSOR GENE PROMOTER VIA DIRECT RECRUITMENT OF DNMT-1 (DNA (CYTOSINE-5)-METHYLTRANSFERASE 1) TO CHROMATIN IN RESPONSE TO TUMOR NECROSIS FACTOR (TNF). TNF-MEDIATED PHOSPHORYLATION OF S276 ON RELA/P65 IS REQUIRED FOR RELA/P65-DNMT-1 INTERACTIONS, CHROMATIN LOADING OF DNMT-1 AND SUBSEQUENT BRMS1 PROMOTER METHYLATION AND TRANSCRIPTIONAL REPRESSION. THE ABILITY OF RELA/P65 TO FUNCTION AS AN ACTIVE TRANSCRIPTIONAL REPRESSOR IS PROMOTER SPECIFIC, AS THE NF-KAPPAB-REGULATED GENE CIAP2 (CELLULAR INHIBITOR OF APOPTOSIS 2) IS TRANSCRIPTIONALLY ACTIVATED WHEREAS BRMS1 IS REPRESSED UNDER IDENTICAL CONDITIONS. SMALL-MOLECULE INHIBITION OF EITHER OF THE MINIMAL INTERACTING DOMAINS BETWEEN RELA/P65-DNMT-1 AND RELA/P65-BRMS1 PROMOTER ABROGATES BRMS1 METHYLATION AND ITS TRANSCRIPTIONAL REPRESSION. THE ABILITY OF RELA/P65 TO DIRECTLY RECRUIT DNMT-1 TO CHROMATIN, RESULTING IN PROMOTER-SPECIFIC METHYLATION AND TRANSCRIPTIONAL REPRESSION OF TUMOR METASTASIS SUPPRESSOR GENE BRMS1, HIGHLIGHTS A NEW MECHANISM THROUGH WHICH NF-KAPPAB CAN REGULATE METASTATIC DISEASE, AND OFFERS A POTENTIAL TARGET FOR NEWER-GENERATION EPIGENETIC ONCOPHARMACEUTICALS. 2012