1 2316 152 EPIGENETIC REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 BY HOST TRANSCRIPTION FACTOR SPECKLED 110 KDA DURING HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV) IS THE LEADING CAUSE OF LIVER DISEASE RANGING FROM ACUTE AND CHRONIC HEPATITIS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). STUDIES HAVE REVEALED THAT HBV INFECTION BROADLY REPROGRAMMES THE HOST CELLULAR METABOLIC PROCESSES FOR VIRAL PATHOGENESIS. PREVIOUS REPORTS HAVE SHOWN THAT GLYCOLYSIS AND GLUCONEOGENESIS ARE AMONG THE MOST DEREGULATED PATHWAYS DURING HBV INFECTION. WE NOTED THAT DESPITE BEING ONE OF THE RATE-LIMITING ENZYMES OF GLUCONEOGENESIS, THE ROLE AND REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 (FBP1) DURING HBV INFECTION IS NOT MUCH EXPLORED. IN THIS STUDY, WE REPORT FBP1 UPREGULATION UPON HBV INFECTION AND UNRAVEL A NOVEL MECHANISM OF EPIGENETIC REPROGRAMMING OF FBP1 BY HBV VIA UTILIZING HOST FACTOR SPECKLED 110 KDA (SP110). HERE, WE IDENTIFIED ACETYLATED LYSINE 18 OF HISTONE H3 (H3K18AC) AS A SELECTIVE INTERACTOR OF SP110 BROMODOMAIN. FURTHERMORE, WE FOUND THAT SP110 GETS RECRUITED ON H3K18AC-ENRICHED FBP1 PROMOTER, AND FACILITATES RECRUITMENT OF DEACETYLASE SIRTUIN 2 (SIRT2) ON THAT SITE IN THE PRESENCE OF HBV. SIRT2 IN TURN BRINGS ITS INTERACTOR AND TRANSCRIPTIONAL ACTIVATOR HEPATOCYTE NUCLEAR FACTOR 4-ALPHA TO THE PROMOTER, WHICH ULTIMATELY LEADS TO A LOSS OF DNA METHYLATION NEAR THE COGNATE SITE. INTERESTINGLY, THIS SP110 DRIVEN FBP1 REGULATION DURING INFECTION WAS FOUND TO PROMOTE VIRAL-BORNE HCC PROGRESSION. MOREOVER, SP110 CAN BE USED AS A PROGNOSTIC MARKER FOR THE HEPATITIS-MEDIATED HCC PATIENTS, WHERE HIGH SP110 EXPRESSION SIGNIFICANTLY LOWERED THEIR SURVIVAL. THUS, THE EPIGENETIC READER PROTEIN SP110 HAS POTENTIAL TO BE A THERAPEUTIC TARGET TO CHALLENGE HBV-INDUCED HCCS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2 6385  45 THE ROLE OF PROMYELOCYTIC LEUKEMIA PROTEIN IN STEATOSIS-ASSOCIATED HEPATIC TUMORS RELATED TO CHRONIC HEPATITIS B VIRUS INFECTION. THE PERSISTENCE OF HEPATITIS B SURFACE ANTIGEN (HBSAG) IS A RISK FACTOR FOR THE DEVELOPMENT OF STEATOSIS-ASSOCIATED TUMORS IN CHRONIC HEPATITIS B VIRUS (HBV) INFECTION, YET LITTLE IS KNOWN ABOUT THE METABOLIC LINK WITH THIS FACTOR. WE CORRELATED HBV-RELATED PATHOGENESIS IN GENETICALLY ENGINEERED MICE AND HUMAN CARRIERS WITH METABOLIC PROTEOMICS AND LIPOGENIC GENE EXPRESSION PROFILES. THE IMMUNOHISTOCHEMISTRY SHOWED THAT THE PROMYELOCYTIC LEUKEMIA PROTEIN (PML, A TUMOR SUPPRESSOR INVOLVED IN GENOME MAINTENANCE AND FATTY ACID OXIDATION), BEING INVERSELY INFLUENCED BY THE DYNAMIC HBSAG LEVELS FROM ACUTE PHASE TO SEROCLEARANCE, APPEARED AS A LIPO-METABOLIC SWITCH LINKING HBSAG-INDUCED STEATOSIS (LIPOGENESIS) TO HBSAG-LOST FAT-BURNING HEPATOCARCINOGENESIS (LIPOLYSIS). KNOCKDOWN OF PML IN HBSAG-TRANSGENIC MICE PREDISPOSED TO OBESITY AND DROVE EARLY STEATOSIS-SPECIFIC LIVER TUMORIGENESIS. PROTEOME ANALYSIS REVEALED THAT THE SIGNALING PATHWAYS CORRESPONDING TO ENERGY METABOLISM AND ITS REGULATORS WERE FREQUENTLY ALTERED BY SUPPRESSION OR DEPLETION OF PML IN THE HBSAG-TRANSGENIC MICE, MAINLY INCLUDING OXIDATIVE PHOSPHORYLATION AND FATTY ACID METABOLISM. EXPRESSION PROFILING FURTHER IDENTIFIED UPREGULATION OF STEAROYL-COA DESATURASE 1 (SCD1) AND EPIGENETIC METHYLATION OF NDUFA13 IN THE MITOCHONDRIAL RESPIRATORY CHAIN AND THE CELL CYCLE INHIBITOR CDKN1C IN CONCORDANCE TO THE INCREASED SEVERITY OF LIPODYSTROPHY AND NEOPLASIA IN THE LIVERS OF HBSAG-TRANSGENIC MICE WITH PML INSUFFICIENCY. THE DEFECT IN LIPOLYSIS IN PML-DEFICIENT HBSAG-TRANSGENIC MICE MADE THE HBSAG-INDUCED ADIPOSE-LIKE LIVER TUMORS VULNERABLE TO SYNTHETIC LETHALITY FROM TOXIC SATURATED FAT ACCUMULATION WITH A SCD1 INHIBITOR. OUR FINDINGS PROVIDE MECHANISTIC INSIGHTS INTO THE EVOLUTION OF STEATOSIS-ASSOCIATED HEPATIC TUMORS DRIVEN BY RECIPROCAL INTERACTIONS OF HBSAG AND PML, AND A POTENTIAL UTILITY OF LIPID METABOLIC REPROGRAMMING AS A TREATMENT TARGET.	2018	
                                                                                                                                                                                                                                                                                            
3 5004  30 PERIPHERAL B CELLS FROM PATIENTS WITH HEPATITIS C VIRUS-ASSOCIATED LYMPHOMA EXHIBIT CLONAL EXPANSION AND AN ANERGIC-LIKE TRANSCRIPTIONAL PROFILE. CHRONIC HCV INFECTION REMAINS A GLOBAL HEALTH CONCERN DUE TO ITS INVOLVEMENT IN HEPATIC AND EXTRAHEPATIC DISEASES, INCLUDING B CELL NON-HODGKIN LYMPHOMA (BNHL). CLINICAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A CAUSAL ROLE FOR HCV IN BNHL DEVELOPMENT, ALTHOUGH MECHANISTIC INSIGHT IS LACKING. WE PERFORMED RNA-SEQUENCING ON PERIPHERAL B CELLS FROM PATIENTS WITH HCV ALONE, BNHL ALONE, AND HCV-ASSOCIATED BNHL TO IDENTIFY UNIQUE AND SHARED TRANSCRIPTIONAL PROFILES ASSOCIATED WITH TRANSFORMATION. IN PATIENTS WITH HCV-ASSOCIATED BNHL, WE OBSERVED THE ENRICHMENT OF AN ANERGIC-LIKE GENE SIGNATURE AND EVIDENCE OF CLONAL EXPANSION THAT WAS CORRELATED WITH THE EXPRESSION OF EPIGENETIC REGULATORY GENES. OUR DATA SUPPORT A ROLE FOR VIRAL-MEDIATED CLONAL EXPANSION OF ANERGIC-LIKE B CELLS IN HCV-ASSOCIATED BNHL DEVELOPMENT AND SUGGEST EPIGENETIC DYSREGULATION AS A POTENTIAL MECHANISM DRIVING EXPANSION. WE PROPOSE EPIGENETIC MECHANISMS MAY BE INVOLVED IN BOTH HCV-ASSOCIATED LYMPHOMA AND REGULATION OF B CELL ANERGY, REPRESENTING AN ATTRACTIVE TARGET FOR CLINICAL INTERVENTIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 3249  40 HEPATITIS B VIRUS HIJACKS CTHRC1 TO EVADE HOST IMMUNITY AND MAINTAIN REPLICATION. HEPATITIS B VIRUS (HBV) INFECTION CAUSES ACUTE AND CHRONIC LIVER DISEASES, BUT IS NOT DIRECTLY CYTOPATHIC. LIVER INJURY RESULTS FROM REPEATED ATTEMPTS OF THE CELLULAR IMMUNE RESPONSE SYSTEM TO CONTROL THE VIRAL INFECTION. HERE, WE INVESTIGATE THE ROLES OF CELLULAR FACTORS AND SIGNALING PATHWAYS INVOLVED IN THE REGULATION OF HBV REPLICATION TO REVEAL THE MECHANISM UNDERLYING HBV INFECTION AND PATHOGENESIS. WE SHOW THAT COLLAGEN TRIPLE HELIX REPEAT CONTAINING 1 (CTHRC1) EXPRESSION IS ELEVATED IN HBV-INFECTED PATIENTS AND IN HBV-TRANSFECTED CELLS THROUGH EPIGENETIC MODIFICATION AND TRANSCRIPTIONAL REGULATION. CTHRC1 FACILITATES HBV REPLICATION IN CULTURED CELLS AND BALB/C MICE BY ACTIVATING THE PKCALPHA/ERK/JNK/C-JUN CASCADE TO REPRESS THE IFN/JAK/STAT PATHWAY. HBV-ACTIVATED CTHRC1 DOWNREGULATES THE ACTIVITY OF TYPE I INTERFERON (IFN), THE PRODUCTION OF IFN-STIMULATED GENES (ISGS), AND THE PHOSPHORYLATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1/2 (STAT1/2), WHEREAS IT UPREGULATES THE PHOSPHORYLATION AND UBIQUITINATION OF TYPE I IFN RECEPTORS (IFNARALPHA/BETA). THUS, OUR RESULTS SHOW THAT HBV USES A NOVEL MECHANISM TO HIJACK CELLULAR FACTORS AND SIGNAL CASCADES IN ORDER TO EVADE HOST ANTIVIRAL IMMUNITY AND MAINTAIN PERSISTENT INFECTION. WE ALSO DEMONSTRATE THAT CTHRC1 HAS A NOVEL ROLE IN VIRAL INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 4233  35 METHYLATION OF SEPTIN9 MEDIATED BY DNMT3A ENHANCES HEPATIC STELLATE CELLS ACTIVATION AND LIVER FIBROGENESIS. LIVER FIBROSIS, RESULTING FROM CHRONIC AND PERSISTENT INJURY TO THE LIVER, IS A WORLDWIDE HEALTH PROBLEM. ADVANCED LIVER FIBROSIS RESULTS IN CIRRHOSIS, LIVER FAILURE AND EVEN HEPATOCELLULAR CANCER (HCC), OFTEN EVENTUALLY REQUIRING LIVER TRANSPLANTATION, POSES A HUGE HEALTH BURDEN ON THE GLOBAL COMMUNITY. HOWEVER, THE SPECIFIC PATHOGENESIS OF LIVER FIBROSIS REMAINS NOT FULLY UNDERSTOOD. NUMEROUS BASIC AND CLINICAL STUDIES HAVE PROVIDED EVIDENCE THAT EPIGENETIC MODIFICATIONS, ESPECIALLY DNA METHYLATION, MIGHT CONTRIBUTE TO THE ACTIVATION OF HEPATIC STELLATE CELLS (HSCS), THE PIVOTAL CELL TYPE RESPONSIBLE FOR THE FIBROUS SCAR IN LIVER. HERE, REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) AND BISULFITE PYROSEQUENCING PCR (BSP) ANALYSIS IDENTIFIED HYPERMETHYLATION STATUS OF SEPTIN9 (SEPT9) GENE IN LIVER FIBROGENESIS. SEPT9 PROTEIN WAS DRAMATICALLY DECREASED IN LIVERS OF CCL4-TREATED MICE AND IMMORTALIZED HSC-T6 CELLS EXPOSED TO TGF-BETA1. NEVERTHELESS, THE SUPPRESSION OF SEPT9 COULD BE BLOCKED BY DNMT3A-SIRNA AND DNA METHYLTRANSFERASE INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE (5-AZADC). OVEREXPRESSED SEPT9 ATTENUATED TGF-BETA1-INDUCED EXPRESSION OF MYOFIBROBLAST MARKERS ALPHA-SMA AND COL1A1, ACCOMPANIED BY UP-REGULATION OF CELL APOPTOSIS-RELATED PROTEINS. CONVERSELY, RNAI-MEDIATED SILENCING OF SEPT9 ENHANCED ACCUMULATION OF EXTRACELLULAR MATRIX. THESE OBSERVATIONS SUGGESTED THAT SEPT9 CONTRIBUTED TO ALLEVIATE LIVER FIBROSIS MIGHT PARTIALLY THROUGH PROMOTING ACTIVATED HSCS APOPTOSIS AND THIS ANTI-FIBROGENESIS EFFECT MIGHT BE BLOCKED BY DNMT-3A MEDIATED METHYLATION OF SEPT9. THEREFORE, PHARMACOLOGICAL AGENTS THAT INHIBIT SEPT9 METHYLATION AND INCREASE ITS EXPRESSION COULD BE CONSIDERED AS VALUABLE TREATMENTS FOR LIVER FIBROSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6 6421  39 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 3327  43 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 5433  25 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9 1334  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 3128  42 GIPC-REGULATED IGFBP-3 PROMOTES HSC MIGRATION IN VITRO AND PORTAL HYPERTENSION IN VIVO THROUGH A BETA1-INTEGRIN PATHWAY. BACKGROUND & AIMS: TRANSFORMING GROWTH FACTOR (TGF-BETA)-INDUCED ACTIVATION OF QUIESCENT HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION TO MYOFIBROBLASTS IS A KEY EVENT IN LIVER FIBROSIS AND PORTAL HYPERTENSION. GIPC (ALSO REFERRED TO AS SYNECTIN) IS A DOWNSTREAM SIGNAL ACTIVATION MOLECULE OF TGF-BETA AND OTHER RECEPTORS. IN THIS STUDY, WE SOUGHT TO IDENTIFY NOVEL GENES TARGETED BY TGF-BETA AND GIPC AND ELUCIDATE IF AND HOW THEY MAY CONTRIBUTE TO LIVER FIBROSIS. METHODS: WE PERFORMED SEQUENTIAL MESSENGER RNA SEQUENCING ANALYSIS ON TGF-BETA-STIMULATED HSCS AND THEN ON TGF-BETA-STIMULATED HSCS IN THE PRESENCE AND ABSENCE OF GIPC ALSO REFERRED TO AS SYNECTIN (GIPC) KNOCKDOWN. INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 (IGFBP-3) TRANSPORT PROTEIN EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC. QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, TARGETED CHROMATIN IMMUNOPRECIPITATION, AND WESTERN BLOT ANALYSIS WERE DONE FOR FURTHER CONFIRMATION. RESULTS: IGFBP-3, AN INSULIN GROWTH FACTOR TRANSPORT PROTEIN, EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC, WHICH WAS CONFIRMED BY QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, AND WESTERN BLOT ANALYSIS. TARGETED CHROMATIN IMMUNOPRECIPITATION SHOWED THAT GIPC INCREASES THE HISTONE 3 LYSINE 27 (H3K27) ACETYLATION ACTIVATING MARK AND CONCURRENTLY DECREASES THE H3K27 INHIBITORY TRIMETHYLATION (H3K27M3) MARK, PROVIDING AN EPIGENETIC CORRELATE TO THE GENE REGULATION CHANGES. IN VIVO, GLOBAL KNOCKOUT OF IGFBP-3 MICE RESULTED IN ATTENUATION OF HSC ACTIVATION MARKERS AND ATTENUATION OF PORTAL PRESSURE IN RESPONSE TO CHRONIC LIVER INJURY MODELS. ANALYSIS OF SERUM LEVELS FROM CIRRHOTIC PATIENTS ALSO SHOWED AN IGFBP-3 INCREASE OF MORE THAN 2-FOLD COMPARED WITH HEALTHY CONTROLS. FINALLY, IN VITRO MECHANISM STUDIES SHOWED THAT IGFBP-3 PROMOTES HSC MIGRATION THROUGH INTEGRIN-DEPENDENT PHOSPHORYLATION OF PROTEIN KINASE B. CONCLUSIONS: TGF-BETA UP-REGULATES IGFBP-3 THROUGH GIPC, LEADING TO INCREASED HSC MIGRATION IN VITRO AND PROMOTES PORTAL HYPERTENSION IN VIVO. THESE STUDIES SUPPORT THE ROLE OF IGFBP-3 AS A POTENTIAL PATHOPHYSIOLOGIC TARGET OR BIOMARKER IN CHRONIC LIVER DISEASE.	2020	

11 3049  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  222  35 ACUTE LIVER STEATOSIS TRANSLATIONALLY CONTROLS THE EPIGENETIC REGULATOR MIER1 TO PROMOTE LIVER REGENERATION IN A STUDY WITH MALE MICE. THE EARLY PHASE LIPID ACCUMULATION IS ESSENTIAL FOR LIVER REGENERATION. HOWEVER, WHETHER THIS ACUTE LIPID ACCUMULATION CAN SERVE AS SIGNALS TO DIRECT LIVER REGENERATION RATHER THAN SIMPLY PROVIDING BUILDING BLOCKS FOR CELL PROLIFERATION REMAINS UNCLEAR. THROUGH IN VIVO CRISPR SCREENING, WE IDENTIFY MIER1 (MESODERM INDUCTION EARLY RESPONSE 1) AS A KEY EPIGENETIC REGULATOR THAT BRIDGES THE ACUTE LIPID ACCUMULATION AND CELL CYCLE GENE EXPRESSION DURING LIVER REGENERATION IN MALE ANIMALS. PHYSIOLOGICALLY, LIVER ACUTE LIPID ACCUMULATION INDUCES THE PHOSPHORYLATION OF EIF2S1(EUKARYOTIC TRANSLATION INITIATION FACTOR 2), WHICH CONSEQUENTLY ATTENUATED MIER1 TRANSLATION. MIER1 DOWNREGULATION IN TURN PROMOTES CELL CYCLE GENE EXPRESSION AND REGENERATION THROUGH CHROMATIN REMODELING. IMPORTANTLY, THE LIPIDS-EIF2S1-MIER1 PATHWAY IS IMPAIRED IN ANIMALS WITH CHRONIC LIVER STEATOSIS; WHEREAS MIER1 DEPLETION SIGNIFICANTLY IMPROVES REGENERATION IN THESE ANIMALS. TAKEN TOGETHER, OUR STUDIES IDENTIFY AN EPIGENETIC MECHANISM BY WHICH THE EARLY PHASE LIPID REDISTRIBUTION FROM ADIPOSE TISSUE TO LIVER DURING REGENERATION IMPACTS HEPATOCYTE PROLIFERATION, AND SUGGEST A POTENTIAL STRATEGY TO BOOST LIVER REGENERATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 4771  42 NUCLEAR SENSOR INTERFERON-INDUCIBLE PROTEIN 16 INHIBITS THE FUNCTION OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA BY INTEGRATING INNATE IMMUNE ACTIVATION AND EPIGENETIC SUPPRESSION. BACKGROUND AND AIMS: NUCLEAR-LOCATED COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) OF HEPATITIS B VIRUS (HBV) IS A DETERMINING FACTOR FOR HBV PERSISTENCE AND THE KEY OBSTACLE FOR A CURE OF CHRONIC HEPATITIS B. HOWEVER, IT REMAINS UNCLEAR WHETHER AND HOW THE HOST IMMUNE SYSTEM SENSES HBV CCCDNA AND ITS BIOLOGICAL CONSEQUENCES. APPROACH AND RESULTS: HERE, WE DEMONSTRATED THAT INTERFERON-INDUCIBLE PROTEIN 16 (IFI16) COULD SERVE AS A UNIQUE INNATE SENSOR TO RECOGNIZE AND BIND TO HBV CCCDNA IN HEPATIC NUCLEI, LEADING TO THE INHIBITION OF CCCDNA TRANSCRIPTION AND HBV REPLICATION. MECHANISTICALLY, OUR DATA SHOWED THAT IFI16 PROMOTED THE EPIGENETIC SUPPRESSION OF HBV CCCDNA BY TARGETING AN INTERFERON-STIMULATED RESPONSE ELEMENT (ISRE) PRESENT IN CCCDNA. IT IS OF INTEREST THAT THIS ISRE WAS ALSO REVEALED TO PLAY AN IMPORTANT ROLE IN IFI16-ACTIVATED TYPE I INTERFERON RESPONSES. FURTHERMORE, OUR DATA REVEALED THAT HBV COULD DOWN-REGULATE THE EXPRESSION LEVEL OF IFI16 IN HEPATOCYTES, AND THERE WAS A NEGATIVE CORRELATION BETWEEN IFI16 AND HBV TRANSCRIPTS IN LIVER BIOPSIES, SUGGESTING THE POSSIBLE ROLE OF IFI16 IN SUPPRESSING CCCDNA FUNCTION UNDER PHYSIOLOGICAL CONDITIONS. CONCLUSIONS: THE NUCLEAR SENSOR IFI16 SUPPRESSES CCCDNA FUNCTION BY INTEGRATING INNATE IMMUNE ACTIVATION AND EPIGENETIC REGULATION BY TARGETING THE ISRE OF CCCDNA, AND IFI16 MAY PRESENT AS A THERAPEUTIC TARGET AGAINST HBV INFECTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14 5678  41 SHORT HAIRPIN RNA INDUCES METHYLATION OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA IN HUMAN HEPATOMA CELLS. SMALL INTERFERING RNAS NOT ONLY MODULATE GENE EXPRESSION AT A POST-TRANSCRIPTIONAL LEVEL, BUT ALSO INDUCE TRANSCRIPTIONAL GENE SILENCING BY RNA INTERFERENCE-MEDIATED HETEROCHROMATIN FORMATION AND RNA-DIRECTED DNA METHYLATION (RDDM). HOWEVER, ALTHOUGH ESTABLISHED IN PLANTS, THERE HAVE BEEN CONTROVERSIES WHETHER RDDM OPERATES IN MAMMALS. HEPATITIS B VIRUS (HBV) COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) SERVES AS A TEMPLATE FOR VIRAL RNA TRANSCRIPTION, AND TRANSCRIPTIONAL ACTIVITY OF HBV CCCDNA IS REGULATED BY METHYLATION IN PATIENTS WITH CHRONIC HBV INFECTION. IN THIS STUDY, WE STABLY EXPRESSED SHORT HAIRPIN RNA (SHRNA) AGAINST HBV IN HUMAN HEPATOMA CELLS TO DETERMINE WHETHER SHRNA INDUCES METHYLATION OF HBV CCCDNA. HEPAD38 CELLS WHICH PERMIT REPLICATION OF HBV UNDER CONTROL OF TETRACYCLINE-RESPONSIVE PROMOTER WERE TRANSDUCED WITH LENTIVIRAL VECTORS WHICH ENCODE SH-1580, A SHRNA AGAINST THE HEPATITIS B VIRAL PROTEIN HBX. BISULFITE SEQUENCING PCR ANALYSIS REVEALED THAT SH-1580 INDUCED CPG METHYLATIONS AT A HIGHER RATE COMPARED TO CONTROL (31.3% VS. 12.8%, P<0.05). THE SH-1580-INDUCED CPG METHYLATION WAS LOCALIZED NEAR THE TARGET SEQUENCE OF SH-1580 IN MORE THAN A HALF OF THE CLONES. METHYLATION-INDUCED TRANSCRIPTIONAL SUPPRESSION WAS CONFIRMED BY IN VITRO TRANSCRIPTION ASSAY. THESE RESULTS CONFIRM THE FEASIBILITY OF RDDM OF HBV CCCDNA IN HUMAN CELLS. LENTIVIRAL VECTOR-MEDIATED TRANSFER OF SHRNA MAY BE USED AS A TOOL FOR NOVEL TRANSCRIPTIONAL MODULATION BY EPIGENETIC MODIFICATION OF HBV CCCDNA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15 3476  42 IDENTIFICATION OF A TRANSMEMBRANE PROTEIN INVOLVED IN SHEAR STRESS SIGNALING AND HEPATOCARCINOGENESIS AFTER A SUSTAINED VIROLOGICAL RESPONSE TO HEPATITIS C VIRUS. BACKGROUND & AIMS: THE RISK OF HEPATOCELLULAR CARCINOMA (HCC) REMAINS AFTER ACHIEVING A SUSTAINED VIROLOGICAL RESPONSE (SVR) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC). EPIGENETIC ABNORMALITIES MIGHT BE KEY REGULATORS IN THE DEVELOPMENT OF HCC. THIS STUDY AIMED TO IDENTIFY THE GENES INVOLVED IN HEPATOCARCINOGENESIS AFTER AN SVR. METHODS: DNA METHYLATION IN LIVER TISSUE WAS COMPARED BETWEEN 21 CHC PATIENTS WITHOUT HCC AND 28 CHC PATIENTS WITH HCC, ALL OF WHOM HAD ACHIEVED AN SVR. ADDITIONAL COMPARISONS WITH 23 CHC PATIENTS BEFORE TREATMENT AND 10 NORMAL LIVERS WERE PERFORMED. THE CHARACTERISTICS OF A NEWLY IDENTIFIED GENE WERE EXPLORED IN VITRO AND IN VIVO. RESULTS: WE FOUND THAT THE TRANSMEMBRANE PROTEIN NO. 164 (TMEM164) GENE WAS DEMETHYLATED BY HEPATITIS C VIRUS INFECTION AND HCC DEVELOPMENT AFTER ACHIEVING AN SVR. TMEM164 WAS EXPRESSED MAINLY IN ENDOTHELIAL CELLS, ALPHA SMOOTH MUSCLE ACTIN-POSITIVE CELLS, AND SOME CAPILLARIZED LIVER SINUSOIDAL ENDOTHELIAL CELLS. TMEM164 EXPRESSION WAS SIGNIFICANTLY CORRELATED WITH LIVER FIBROSIS AND RELAPSE-FREE SURVIVAL IN HCC PATIENTS. TMEM164 WAS INDUCED BY SHEAR STRESS, INTERACTED WITH GRP78/BIP, ACCELERATED ATF6 (ACTIVATING TRANSCRIPTION FACTOR 6)-MEDIATED ENDOPLASMIC RETICULUM (ER) STRESS SIGNALING, AND ACTIVATED INTERLEUKIN-6/STAT3 (SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3) SIGNALING IN THE TMNK1 LIVER ENDOTHELIAL CELL LINE. THEREFORE, WE TERMED TMEM164 "SHEAR STRESS-INDUCED TRANSMEMBRANE PROTEIN ASSOCIATED WITH ER STRESS SIGNALING" (SHERMER). SHERMER KNOCKOUT MICE WERE PROTECTED AGAINST CCL4-INDUCED LIVER FIBROSIS. SHERMER OVEREXPRESSION IN TMNK1 CELLS ACCELERATED HCC GROWTH IN A XENOGRAFT MODEL. CONCLUSIONS: WE IDENTIFIED A NEW TRANSMEMBRANE PROTEIN, SHERMER, IN CHC PATIENTS WITH HCC AFTER ACHIEVING AN SVR. SHERMER WAS INDUCED BY SHEAR STRESS AND ACCELERATED ATF6-MEDIATED ER STRESS SIGNALING IN ENDOTHELIAL CELLS. THUS, SHERMER IS A NOVEL ENDOTHELIAL MARKER ASSOCIATED WITH LIVER FIBROSIS, HEPATOCARCINOGENESIS, AND PROGRESSION OF HCC.	2023	
                                                                                                                                                                      
16 5153  26 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 3728  30 INHIBITION OF REPLICATION OF HEPATITIS B VIRUS USING TRANSCRIPTIONAL REPRESSORS THAT TARGET THE VIRAL DNA. BACKGROUND: CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) IS A SERIOUS GLOBAL HEALTH PROBLEM. PERSISTENCE OF THE VIRUS OCCURS AS A RESULT OF STABILITY OF THE REPLICATION INTERMEDIATE COMPRISING COVALENTLY CLOSED CIRCULAR DNA (CCCDNA). DEVELOPMENT OF DRUGS THAT ARE CAPABLE OF DISABLING THIS CCCDNA IS VITAL. METHODS: TO INVESTIGATE AN EPIGENETIC APPROACH TO INACTIVATING VIRAL DNA, WE ENGINEERED TRANSCRIPTIONAL REPRESSORS THAT COMPRISE AN HBV DNA-BINDING DOMAIN OF TRANSCRIPTION ACTIVATOR LIKE EFFECTORS (TALES) AND A FUSED KRUPPEL ASSOCIATED BOX (KRAB). THESE REPRESSOR TALES (RTALES) TARGETED THE VIRAL SURFACE OPEN READING FRAME AND WERE PLACED UNDER TRANSCRIPTION CONTROL OF CONSTITUTIVELY ACTIVE OR LIVER-SPECIFIC PROMOTERS. RESULTS: EVALUATION IN CULTURED CELLS AND FOLLOWING HYDRODYNAMIC INJECTION OF MICE REVEALED THAT THE RTALES SIGNIFICANTLY INHIBITED PRODUCTION OF MARKERS OF HBV REPLICATION WITHOUT EVIDENCE OF HEPATOTOXICITY. INCREASED METHYLATION OF HBV DNA AT CPG ISLAND II SHOWED THAT THE RTALES CAUSED INTENDED EPIGENETIC MODIFICATION. CONCLUSIONS: EPIGENETIC MODIFICATION OF HBV DNA IS A NEW AND EFFECTIVE MEANS OF INACTIVATING THE VIRUS IN VIVO. THE APPROACH HAS THERAPEUTIC POTENTIAL AND AVOIDS POTENTIALLY PROBLEMATIC UNINTENDED MUTAGENESIS OF GENE EDITING.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18 2432  39 EPIGENETIC SILENCING OF MIR-708 ENHANCES NF-KAPPAB SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MICRORNAS (MIRNAS) ARE POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION AND THEIR DEREGULATION IS INVOLVED IN TUMOR DEVELOPMENT. EPIGENETIC GENE SILENCING IN CANCER BY DNA METHYLATION CONTRIBUTES TO THE SILENCING OF TUMOR-SUPPRESSOR GENES, INCLUDING MIRNAS. WE HAVE RECENTLY SHOWN THAT THE PROMOTER OF MIR-708 IS ABERRANTLY METHYLATED IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). TO CHARACTERIZE THE MOLECULAR SIGNALING NETWORKS THAT ARE INFLUENCED BY MIR-708, WE PERFORMED A LUCIFERASE-BASED SCREEN EVALUATING THE EFFECTS OF ECTOPIC MIR-708 EXPRESSION ON LEUKEMIA-RELEVANT SIGNALING PATHWAYS. WE FOUND THAT MIR-708 STRONGLY REPRESSED NF-KAPPAB SIGNALING, A PATHWAY KNOWN TO BE DEREGULATED IN CLL. AMONG THE PREDICTED MIR-708 TARGETS WAS IKKBETA (INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE-BETA/IKBKB), A KEY KINASE FACILITATING NF-KAPPAB SIGNALING. WE VALIDATED THE INTERACTION OF MIR-708 WITH THE 3'-UNTRANSLATED REGION OF IKKBETA AND FOUND THAT MIR-708 OVEREXPRESSION REPRESSES ENDOGENOUS IKKBETA. PHOSPHORYLATION OF THE IKKBETA TARGET IKAPPABALPHA AND EXPRESSION OF KNOWN NF-KAPPAB TARGET GENES WERE IMPAIRED BY MIR-708. FURTHERMORE, WE IDENTIFIED AN ENHANCER REGION DOWNSTREAM OF THE MIR-708 PROMOTER THAT DISPLAYS A DISTINCT DNA METHYLATION STATUS IN CLL. HIGH ENHANCER METHYLATION IS SIGNIFICANTLY CORRELATED WITH LOWER MIR-708 EXPRESSION AND IS PREDOMINANTLY FOUND IN PATIENTS WITH POOR PROGNOSIS AND SHORTER TIME TO TREATMENT. THESE RESULTS DEMONSTRATE THAT MIR-708 REGULATES THE NF-KAPPAB PATHWAY BY TARGETING IKKBETA, AND THAT METHYLATION OF A KEY ENHANCER REGION CONTRIBUTES TO ITS SUPPRESSION IN CLL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 3762  37 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER.	2022	
                                                                                                                                                                                                                                                     
20 1966  29 EPIGENETIC ALTERATION OF PRKCDBP IN COLORECTAL CANCERS AND ITS IMPLICATION IN TUMOR CELL RESISTANCE TO TNFALPHA-INDUCED APOPTOSIS. PURPOSE: PRKCDBP IS A PUTATIVE TUMOR SUPPRESSOR IN WHICH ALTERATION HAS BEEN OBSERVED IN SEVERAL HUMAN CANCERS. WE INVESTIGATED EXPRESSION AND FUNCTION OF PRKCDBP IN COLORECTAL CELLS AND TISSUES TO EXPLORE ITS CANDIDACY AS A SUPPRESSOR IN COLORECTAL TUMORIGENESIS. EXPERIMENTAL DESIGN: EXPRESSION AND METHYLATION STATUS OF PRKCDBP AND ITS EFFECT ON TUMOR GROWTH WERE EVALUATED. TRANSCRIPTIONAL REGULATION BY NF-KAPPAB SIGNALING WAS DEFINED BY LUCIFERASE REPORTER AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: PRKCDBP EXPRESSION WAS HARDLY DETECTABLE IN 29 OF 80 (36%) PRIMARY TUMORS AND 11 OF 19 (58%) CELL LINES, AND ITS ALTERATION CORRELATED WITH TUMOR STAGE AND GRADE. PROMOTER HYPERMETHYLATION WAS COMMONLY FOUND IN CANCERS. PRKCDBP EXPRESSION INDUCED THE G(1) CELL-CYCLE ARREST AND INCREASED CELLULAR SENSITIVITY TO VARIOUS APOPTOTIC STRESSES. PRKCDBP WAS INDUCED BY TNFALPHA, AND ITS LEVEL CORRELATED WITH TUMOR CELL SENSITIVITY TO TNFALPHA-INDUCED APOPTOSIS. PRKCDBP INDUCTION BY TNFALPHA WAS DISRUPTED BY BLOCKING NF-KAPPAB SIGNALING WHILE IT WAS ENHANCED BY RELA TRANSFECTION. THE PRKCDBP PROMOTER ACTIVITY WAS INCREASED IN RESPONSE TO TNFALPHA, AND THIS RESPONSE WAS ABOLISHED BY DISRUPTION OF A KAPPAB SITE IN THE PROMOTER. PRKCDBP DELAYED THE FORMATION AND GROWTH OF XENOGRAFT TUMORS AND IMPROVED TUMOR RESPONSE TO TNFALPHA-INDUCED APOPTOSIS. CONCLUSIONS: PRKCDBP IS A PROAPOPTOTIC TUMOR SUPPRESSOR WHICH IS COMMONLY ALTERED IN COLORECTAL CANCER BY PROMOTER HYPERMETHYLATION, AND ITS GENE TRANSCRIPTION IS DIRECTLY ACTIVATED BY NF-KAPPAB IN RESPONSE TO TNFALPHA. THIS SUGGESTS THAT PRKCDBP INACTIVATION MAY CONTRIBUTE TO TUMOR PROGRESSION BY REDUCING CELLULAR SENSITIVITY TO TNFALPHA AND OTHER STRESSES, PARTICULARLY UNDER CHRONIC INFLAMMATORY MICROENVIRONMENT.	2011