1 3948 120 LNCRNA-CD160 DECREASES THE IMMUNITY OF CD8(+) T CELLS THROUGH EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS INFECTION. THE TRANSFER AND DEVELOPMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ASSOCIATED WITH THE T CELL IMMUNE RESPONSE, THEREFORE INVESTIGATING THE KEY REGULATORS OF CELL IMMUNE RESPONSE IS NEEDED TO IMPROVE CHRONIC HBV TREATMENT. BLOOD SAMPLES FROM PATIENTS WITH CHRONIC HBV INFECTION WERE USED TO CONFIRM THE CORRELATION BETWEEN HBV INFECTION STAGE AND CD160 RECEPTOR EXPRESSION LEVELS IN CD8(+) T CELLS, THE CD8(+) T CELLS ARE USED TO RESEARCH THE MECHANISM OF T CELL IMMUNE RESPONSE MODULATION, MOREOVER, C3H/HEN MICE WITH REDUCED CD160 EXPRESSION LEVELS WERE USED TO INVESTIGATE THE ASSOCIATION BETWEEN LONG NON-CODING (LNC)RNA-CD160 AND HBV INFECTION. LONG NON-CODING (LNC)RNA-CD160 AND HISTONE-MODIFICATION ENZYME GENE HISTONE DEACETYLASE 11 (HDAC11) EXPRESSION LEVELS WERE NEGATIVELY ASSOCIATED WITH CD160 EXPRESSION. LNCRNA-CD160 CAN INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA THROUGH HDAC11 RECRUITMENT AND BIND TO HDAC11 TO FORM A COMPLEX ON THE PROMOTERS OF IFN-GAMMA AND TNF-ALPHA. THE HDAC11, IFN-GAMMA AND TNF-ALPHA FORM A COMPLEX AND ENHANCE THE METHYLATION OF H3K9ME1, CHROMATIN CHANGES INTO THE HETEROCHROMATIN AND THE TRANSCRIPTION OF IFN-GAMMA AND TNF-ALPHA IS BLOCKED; MOREOVER, THE HDAC11/IFN-GAMMA/TNF-ALPHA COMPLEX CAN ALSO INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA IN CD160(-) CD8(+) T CELLS AND SUPPRESSES THE FUNCTION OF CD8(+) T CELLS. FURTHERMORE, SMALL INTERFERING RNA TARGETING LNCRNA-CD160 CAN BLOCK HBV INFECTION PROGRESSION. LNCRNA-CD160 ACTS AS AN IMMUNE SUPPRESSIVE FACTOR AND IS EXPRESSED AT A HIGH LEVEL IN PERIPHERAL BLOOD CD8(+) T CELLS OF HBV INFECTED PATIENTS. FURTHERMORE, HIGH EXPRESSION LEVELS OF LNCRNA-CD160 CAN CONTRIBUTE TO THE INHIBITION OF IFN-GAMMA AND TNF-ALPHA SECRETION IN CD8(+) T CELLS AND DECREASE THE IMMUNE RESPONSE OF CD8(+) T CELLS. THEREFORE, LNCRNA-CD160 MAY BECOME A NEW TARGET FOR IMMUNOTHERAPY OF CHRONIC HBV INFECTION IN THE FUTURE AND MAY PROVIDE A NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF HBV INFECTION. 2020 2 5918 31 TARGETING BMI-1 IN B CELLS RESTORES EFFECTIVE HUMORAL IMMUNE RESPONSES AND CONTROLS CHRONIC VIRAL INFECTION. INEFFECTIVE ANTIBODY-MEDIATED RESPONSES ARE A KEY CHARACTERISTIC OF CHRONIC VIRAL INFECTION. HOWEVER, OUR UNDERSTANDING OF THE INTRINSIC MECHANISMS THAT DRIVE THIS DYSREGULATION ARE UNCLEAR. HERE, WE IDENTIFY THAT TARGETING THE EPIGENETIC MODIFIER BMI-1 IN MICE IMPROVES HUMORAL RESPONSES TO CHRONIC LYMPHOCYTIC CHORIOMENINGITIS VIRUS. BMI-1 WAS UPREGULATED BY GERMINAL CENTER B CELLS IN CHRONIC VIRAL INFECTION, CORRELATING WITH CHANGES TO THE ACCESSIBLE CHROMATIN LANDSCAPE, COMPARED TO ACUTE INFECTION. B CELL-INTRINSIC DELETION OF BMI1 ACCELERATED VIRAL CLEARANCE, REDUCED SPLENOMEGALY AND RESTORED SPLENIC ARCHITECTURE. DELETION OF BMI1 RESTORED C-MYC EXPRESSION IN B CELLS, CONCOMITANT WITH IMPROVED QUALITY OF ANTIBODY AND COUPLED WITH REDUCED ANTIBODY-SECRETING CELL NUMBERS. SPECIFICALLY, BMI-1-DEFICIENCY INDUCED ANTIBODY WITH INCREASED NEUTRALIZING CAPACITY AND ENHANCED ANTIBODY-DEPENDENT EFFECTOR FUNCTION. USING A SMALL MOLECULE INHIBITOR TO MURINE BMI-1, WE COULD DEPLETE ANTIBODY-SECRETING CELLS AND PROHIBIT DETRIMENTAL IMMUNE COMPLEX FORMATION IN VIVO. THIS STUDY DEFINES BMI-1 AS A CRUCIAL IMMUNE MODIFIER THAT CONTROLS ANTIBODY-MEDIATED RESPONSES IN CHRONIC INFECTION. 2022 3 1763 29 EARLY TRANSCRIPTIONAL AND EPIGENETIC DIVERGENCE OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTION. DURING A MICROBIAL INFECTION, RESPONDING CD8+ T CELLS GIVE RISE TO EFFECTOR CELLS THAT PROVIDE ACUTE HOST DEFENSE AND MEMORY CELLS THAT PROVIDE SUSTAINED PROTECTION. AN ALTERNATIVE OUTCOME IS EXHAUSTION, A STATE OF T CELL DYSFUNCTION THAT OCCURS IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCER. ALTHOUGH IT IS EVIDENT THAT EXHAUSTED CD8+ T (TEX) CELLS ARE PHENOTYPICALLY AND MOLECULARLY DISTINCT FROM EFFECTOR AND MEMORY CD8+ T CELLS, THE FACTORS REGULATING THE EARLIEST EVENTS IN THE DIFFERENTIATION PROCESS OF TEX CELLS REMAIN INCOMPLETELY UNDERSTOOD. HERE, WE PERFORMED SINGLE-CELL RNA-SEQUENCING AND SINGLE-CELL ATAC-SEQUENCING OF CD8+ T CELLS RESPONDING TO LCMV-ARMSTRONG (LCMV-ARM) OR LCMV-CLONE 13 (LCMV-CL13), WHICH RESULT IN ACUTE OR CHRONIC INFECTIONS, RESPECTIVELY. COMPARED TO CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-ARM (DIV1ARM) CELLS, CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-CL13 (DIV1CL13) EXPRESSED HIGHER LEVELS OF GENES ENCODING TRANSCRIPTION FACTORS PREVIOUSLY ASSOCIATED WITH EXHAUSTION, ALONG WITH HIGHER LEVELS OF EZH2, THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COMPLEX, WHICH MEDIATES EPIGENETIC SILENCING. MODULATION OF EZH2 RESULTED IN ALTERED EXPRESSION OF EXHAUSTION-ASSOCIATED MOLECULES BY CD8+ T CELLS RESPONDING TO LCMV-CL13, THOUGH THE SPECIFIC CELLULAR AND INFECTIOUS CONTEXTS, RATHER THAN SIMPLY THE LEVEL OF EZH2 EXPRESSION, LIKELY DETERMINE THE EVENTUAL OUTCOME. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THE DIFFERENTIATION PATHS OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTIONS MAY DIVERGE EARLIER THAN PREVIOUSLY APPRECIATED. 2023 4 3728 33 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 5 1902 28 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 6 6421 33 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 7 819 36 CHARACTERIZATION OF A KDM5 SMALL MOLECULE INHIBITOR WITH ANTIVIRAL ACTIVITY AGAINST HEPATITIS B VIRUS. CHRONIC HEPATITIS B (CHB) IS A GLOBAL HEALTH CARE CHALLENGE AND A MAJOR CAUSE OF LIVER DISEASE. TO FIND NEW THERAPEUTIC AVENUES WITH A POTENTIAL TO FUNCTIONALLY CURE CHRONIC HEPATITIS B VIRUS (HBV) INFECTION, WE PERFORMED A FOCUSED SCREEN OF EPIGENETIC MODIFIERS TO IDENTIFY POTENTIAL INHIBITORS OF REPLICATION OR GENE EXPRESSION. FROM THIS WORK WE IDENTIFIED ISONICOTINIC ACID INHIBITORS OF THE HISTONE LYSINE DEMETHYLASE 5 (KDM5) WITH POTENT ANTI-HBV ACTIVITY. TO ENHANCE THE CELLULAR PERMEABILITY AND LIVER ACCUMULATION OF THE MOST POTENT KDM5 INHIBITOR IDENTIFIED (GS-080) AN ESTER PRODRUG WAS DEVELOPED (GS-5801) THAT RESULTED IN IMPROVED BIOAVAILABILITY AND LIVER EXPOSURE AS WELL AS AN INCREASED H3K4ME3:H3 RATIO ON CHROMATIN. GS-5801 TREATMENT OF HBV-INFECTED PRIMARY HUMAN HEPATOCYTES REDUCED THE LEVELS OF HBV RNA, DNA AND ANTIGEN. EVALUATION OF GS-5801 ANTIVIRAL ACTIVITY IN A HUMANIZED MOUSE MODEL OF HBV INFECTION, HOWEVER, DID NOT RESULT IN ANTIVIRAL EFFICACY, DESPITE ACHIEVING PHARMACODYNAMIC LEVELS OF H3K4ME3:H3 PREDICTED TO BE EFFICACIOUS FROM THE IN VITRO MODEL. HERE WE DISCUSS POTENTIAL REASONS FOR THE DISCONNECT BETWEEN IN VITRO AND IN VIVO EFFICACY, WHICH HIGHLIGHT THE TRANSLATIONAL DIFFICULTIES OF EPIGENETIC TARGETS FOR VIRAL DISEASES. 2022 8 2146 35 EPIGENETIC MANIPULATION RESTORES FUNCTIONS OF DEFECTIVE CD8(+) T CELLS FROM CHRONIC VIRAL INFECTION. FUNCTIONAL EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS IS A DEFINING CHARACTERISTIC OF MANY CHRONIC INFECTIONS, BUT THE UNDERLYING MECHANISMS OF T CELL DYSFUNCTION ARE NOT WELL UNDERSTOOD. EPIGENETICS PLAYS AN IMPORTANT ROLE IN THE CONTROL OF T CELL DEVELOPMENT, DIFFERENTIATION, AND FUNCTION. TO EXAMINE IF EPIGENETICS ALSO PLAYS A ROLE IN T CELL EXHAUSTION, WE ANALYZED CHROMATIN REMODELING IN CD8(+) T CELLS FROM MICE WITH CHRONIC LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION. WE OBSERVED DOWNREGULATION OF DIACETYLATED HISTONE H3 IN BOTH VIRUS-SPECIFIC AND TOTAL CD8(+) T CELLS, AND FUNCTIONAL DEFECTS NOT ONLY IN VIRUS-SPECIFIC CD8(+) T CELLS BUT ALSO WITHIN THE TOTAL CD8(+) T CELL POPULATION. IN VITRO TREATMENT OF THESE EXHAUSTED CD8(+) T CELLS WITH HISTONE DEACETYLASE INHIBITORS RESTORED DIACETYLATED HISTONE H3 LEVELS, AND IMPROVED THEIR IMMUNE FUNCTIONS. UPON ADOPTIVE TRANSFER, THESE TREATED CD8(+) T CELLS DEVELOPED INTO FUNCTIONAL MEMORY T CELLS IN VIVO THAT ENHANCED PROTECTIVE IMMUNITY. THESE RESULTS DEFINE A ROLE OF EPIGENETICS IN T CELL EXHAUSTION AND SUGGEST EPIGENETIC MANIPULATION AS A NOVEL MOLECULAR THERAPY TO RESTORE IMMUNE FUNCTIONS. 2014 9 4771 40 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 10 6057 29 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 11 194 34 ACETYLSHIKONIN SUPPRESSES INVASION OF PORPHYROMONAS GINGIVALIS?INFECTED YD10B ORAL CANCER CELLS BY MODULATING THE INTERLEUKIN-8/MATRIX METALLOPROTEINASE AXIS. THE DEVELOPMENT OF PHARMACEUTICAL AGENTS POSSESSING ANTI?INVASIVE AND ANTI?METASTATIC ABILITIES, AS WELL AS APOPTOTIC ACTIVITY, IS IMPORTANT IN DECREASING THE INCIDENCE AND RECURRENCE OF ORAL CANCER. CANCER CELLS ARE KNOWN TO ACQUIRE INVASIVENESS NOT ONLY THROUGH EPIGENETIC CHANGES, BUT ALSO FROM INFLAMMATORY STIMULI WITHIN THE TUMOR MICROENVIRONMENT. ACCORDINGLY, THE IDENTIFICATION OF AGENTS THAT CAN SUPPRESS THE INFLAMMATION?PROMOTED INVASIVENESS OF CANCER CELLS MAY BE IMPORTANT IN TREATING CANCER AND IMPROVING THE PROGNOSIS OF PATIENTS WITH CANCER. ACETYLSHIKONIN, A FLAVONOID WITH ANTI?INFLAMMATORY ACTIVITY, INHIBITS PROLIFERATION AND INDUCES APOPTOSIS OF ORAL CANCER CELLS. IN THE PRESENT STUDY, THE ANTI?INVASIVE EFFECT OF ACETYLSHIKONIN ON YD10B ORAL CANCER CELLS INFECTED WITH PORPHYROMONAS GINGIVALIS, A MAJOR PATHOGEN OF CHRONIC PERIODONTITIS, AND THE MECHANISMS INVOLVED WERE INVESTIGATED. FIRSTLY, WE EXAMINED WHETHER P. GINGIVALIS INFECTION INCREASED THE INVASIVENESS OF YD10B CELLS. RESULTS SUGGESTED THAT YD10B ORAL CANCER CELLS BECOME MORE AGGRESSIVE WHEN THEY ARE INFECTED WITH P. GINGIVALIS. SECONDLY, ACETYLSHIKONIN SIGNIFICANTLY INHIBITED THE INVASION OF P. GINGIVALIS?INFECTED YD10B CELLS BY SUPPRESSING IL?8 RELEASE AND IL?8?DEPENDENT MMP RELEASE. THESE DATA SUGGEST THAT ACETYLSHIKONIN MAY BE A USEFUL PREVENTIVE AND THERAPEUTIC CANDIDATE FOR ORAL CANCER THAT IS CHRONICALLY INFECTED WITH PERIODONTAL PATHOGENS. 2018 12 4866 31 ORTHOGONAL CRISPR SCREENS TO IDENTIFY TRANSCRIPTIONAL AND EPIGENETIC REGULATORS OF HUMAN CD8 T CELL FUNCTION. THE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPIES IS STRONGLY ASSOCIATED WITH TRANSCRIPTIONAL AND EPIGENETIC STATE. THUS, TECHNOLOGIES TO DISCOVER REGULATORS OF T CELL GENE NETWORKS AND THEIR CORRESPONDING PHENOTYPES HAVE GREAT POTENTIAL TO IMPROVE THE EFFICACY OF T CELL THERAPIES. WE DEVELOPED POOLED CRISPR SCREENING APPROACHES WITH COMPACT EPIGENOME EDITORS TO SYSTEMATICALLY PROFILE THE EFFECTS OF ACTIVATION AND REPRESSION OF 120 TRANSCRIPTION FACTORS AND EPIGENETIC MODIFIERS ON HUMAN CD8+ T CELL STATE. THESE SCREENS NOMINATED KNOWN AND NOVEL REGULATORS OF T CELL PHENOTYPES WITH BATF3 EMERGING AS A HIGH CONFIDENCE GENE IN BOTH SCREENS. WE FOUND THAT BATF3 OVEREXPRESSION PROMOTED SPECIFIC FEATURES OF MEMORY T CELLS SUCH AS INCREASED IL7R EXPRESSION AND GLYCOLYTIC CAPACITY, WHILE ATTENUATING GENE PROGRAMS ASSOCIATED WITH CYTOTOXICITY, REGULATORY T CELL FUNCTION, AND T CELL EXHAUSTION. IN THE CONTEXT OF CHRONIC ANTIGEN STIMULATION, BATF3 OVEREXPRESSION COUNTERED PHENOTYPIC AND EPIGENETIC SIGNATURES OF T CELL EXHAUSTION. CAR T CELLS OVEREXPRESSING BATF3 SIGNIFICANTLY OUTPERFORMED CONTROL CAR T CELLS IN BOTH IN VITRO AND IN VIVO TUMOR MODELS. MOREOVER, WE FOUND THAT BATF3 PROGRAMMED A TRANSCRIPTIONAL PROFILE THAT CORRELATED WITH POSITIVE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPY. FINALLY, WE PERFORMED CRISPR KNOCKOUT SCREENS WITH AND WITHOUT BATF3 OVEREXPRESSION TO DEFINE CO-FACTORS AND DOWNSTREAM FACTORS OF BATF3, AS WELL AS OTHER THERAPEUTIC TARGETS. THESE SCREENS POINTED TO A MODEL WHERE BATF3 INTERACTS WITH JUNB AND IRF4 TO REGULATE GENE EXPRESSION AND ILLUMINATED SEVERAL OTHER NOVEL TARGETS FOR FURTHER INVESTIGATION. 2023 13 2389 35 EPIGENETIC REPOLARIZATION OF T LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS USING 5-AZA-2'-DEOXYCYTIDINE. T CELL IMMUNE DYSFUNCTION HAS AN IMPORTANT ROLE IN THE PROFOUND IMMUNE SUPPRESSION THAT CHARACTERIZES CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). IMPROPER POLARIZATION OF T CELLS HAS BEEN PROPOSED AS ONE OF THE MECHANISM INVOLVED. MOUNTING DATA IMPLICATES CHROMATIN REGULATION, NAMELY PROMOTER METHYLATION, IN THE PLASTICITY OF NAIVE HUMAN T CELLS. RECENT IN VITRO EVIDENCE INDICATES THAT THIS PLASTICITY MAY BE PHENOTYPICALLY ALTERED BY USING METHYLATION INHIBITORS WHICH ARE APPROVED FOR CLINICAL USE IN CERTAIN TYPES OF CANCER. THESE RESULTS BEG THE QUESTION: CAN THE INEFFECTIVE POLARIZATION OF T LYMPHOCYTES IN THE CONTEXT OF CLL BE EFFECTIVELY MODULATED USING METHYLATION INHIBITORS IN A SUSTAINABLE THERAPEUTIC FASHION? TO ANSWER THIS QUESTION OUR LABORATORY HAS STUDIED THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (5A2) IN HELPER AND CYTOTOXIC T LYMPHOCYTES FROM HEALTHY DONORS AND CLL PATIENTS IN WELL CHARACTERIZED MOLECULAR AND EPIGENETIC SIGNALING PATHWAYS INVOLVED IN EFFECTIVE POLARIZATION. MOREOVER, WE SOUGHT TO INVESTIGATE THE CONSEQUENCES OF METHYLATION INHIBITOR TREATMENT ON LYMPHOCYTE SURVIVAL, ACTIVATION INTENSITY, AND NAIVE CELL POLARIZATION. OUR DATA INDICATES THAT 5A2 TREATMENT CAN DEPOLARIZE TH2 CELLS TO EFFECTIVELY SECRETE INTERFERON GAMMA, SIGNAL VIA T-BET, AND ACHIEVE DEMETHYLATION OF CRITICAL TH1 SPECIFIC PROMOTERS. MOREOVER, WE DEMONSTRATE THAT 5A2 CAN FORCE TH1 POLARIZATION OF NAIVE T CELLS DESPITE A STRONG IL-4 STIMULI AND A LACK OF IL-12. IN CONCLUSION OUR DATA SEEKS TO DEFINE A MODALITY IN WHICH IMPROPER OR INEFFECTIVE T CELL POLARIZATION CAN BE ALTERED BY 5AZA AND COULD BE INCORPORATED IN FUTURE THERAPEUTIC INTERVENTIONS. 2011 14 6209 34 THE INTERFERON-STIMULATED GENE TRIM22: A DOUBLE-EDGED SWORD IN HIV-1 INFECTION. INFECTION OF TARGET CELLS BY THE HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV-1) IS HAMPERED BY CONSTITUTIVELY EXPRESSED HOST CELL PROTEINS PREVENTING OR CURTAILING VIRUS REPLICATION AND THEREFORE DEFINED AS "RESTRICTION FACTORS". AMONG THEM, MEMBERS OF THE TRIPARTITE MOTIF (TRIM) FAMILY HAVE EMERGED AS IMPORTANT PLAYERS ENDOWED WITH BOTH ANTIVIRAL EFFECTS AND MODULATORY CAPACITY OF THE INNATE IMMUNE RESPONSE. TRIM5ALPHA AND TRIM19 (I.E. PROMYELOCYTIC LEUKEMIA, PML) ARE AMONG THE BEST-CHARACTERIZED FAMILY MEMBERS; HOWEVER, IN THIS REVIEW WE WILL FOCUS ON THE POTENTIAL ROLE OF ANOTHER FAMILY MEMBER, I.E. TRIM22, A FACTOR STRONGLY INDUCED BY INTERFERON STIMULATION, IN HIV INFECTION IN VIVO AND IN VITRO IN THE CONTEXT OF ITS BROADER ANTIVIRAL EFFECTS. WE WILL ALSO FOCUS ON THE POTENTIAL ROLE OF TRIM22 IN HIV-1-INFECTED INDIVIDUALS SPECULATING ON ITS DUAL ROLE IN CONTROLLING VIRUS REPLICATION AND MORE COMPLEX ROLE IN CHRONIC INFECTION. AT THE MOLECULAR LEVELS, WE WILL REVIEW THE EVIDENCE IN FAVOR OF A RELEVANT ROLE OF TRIM22 AS EPIGENETIC INHIBITOR OF HIV-1 TRANSCRIPTION ACTING BY PREVENTING THE BINDING OF THE HOST CELL TRANSCRIPTION FACTOR SP1 TO THE VIRAL PROMOTER. THESE EVIDENCES SUGGEST THAT TRIM22 SHOULD BE CONSIDERED A POTENTIAL NEW PLAYER IN EITHER THE ESTABLISHMENT OR MAINTENANCE OF HIV-1 RESERVOIRS OF LATENTLY INFECTED CELLS UNAFFECTED BY COMBINATION ANTIRETROVIRAL THERAPY. 2018 15 222 28 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 16 2446 25 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 17 6294 30 THE PROINFLAMMATORY CYTOKINE TNFALPHA INDUCES DNA DEMETHYLATION-DEPENDENT AND -INDEPENDENT ACTIVATION OF INTERLEUKIN-32 EXPRESSION. IL-32 IS A CYTOKINE INVOLVED IN PROINFLAMMATORY IMMUNE RESPONSES TO BACTERIAL AND VIRAL INFECTIONS. HOWEVER, THE ROLE OF EPIGENETIC EVENTS IN THE REGULATION OF IL-32 GENE EXPRESSION IS UNDERSTUDIED. HERE WE SHOW THAT IL-32 IS REPRESSED BY DNA METHYLATION IN HEK293 CELLS. USING CHIP SEQUENCING, LOCUS-SPECIFIC METHYLATION ANALYSIS, CRISPR/CAS9-MEDIATED GENOME EDITING, AND RT-QPCR (QUANTITATIVE RT-PCR) AND IMMUNOBLOT ASSAYS, WE FOUND THAT SHORT-TERM TREATMENT (A FEW HOURS) WITH THE PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) ACTIVATES IL-32 IN A DNA DEMETHYLATION-INDEPENDENT MANNER. IN CONTRAST, PROLONGED TNFALPHA TREATMENT (SEVERAL DAYS) INDUCED DNA DEMETHYLATION AT THE PROMOTER AND A CPG ISLAND IN THE IL-32 GENE IN A TET (TEN-ELEVEN TRANSLOCATION) FAMILY ENZYME- AND NF-KAPPAB-DEPENDENT MANNER. NOTABLY, THE HYPOMETHYLATION STATUS OF TRANSCRIPTIONAL REGULATORY ELEMENTS IN IL-32 WAS MAINTAINED FOR A LONG TIME (SEVERAL WEEKS), CAUSING ELEVATED IL-32 EXPRESSION EVEN IN THE ABSENCE OF TNFALPHA. CONSIDERING THAT IL-32 CAN, IN TURN, INDUCE TNFALPHA EXPRESSION, WE SPECULATE THAT SUCH FEEDFORWARD EVENTS MAY CONTRIBUTE TO THE TRANSITION FROM AN ACUTE INFLAMMATORY RESPONSE TO CHRONIC INFLAMMATION. 2019 18 5476 33 RESTORING T CELL TOLERANCE, EXPLORING THE POTENTIAL OF HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS CHARACTERIZED BY A LOSS OF IMMUNE TOLERANCE. HERE, THE BALANCE BETWEEN THE ACTIVITY OF EFFECTOR T (TEFF) CELLS AND REGULATORY T (TREG) CELLS IS DISTURBED RESULTING IN CHRONIC INFLAMMATION IN THE JOINTS. PRESENTLY, THERAPEUTIC STRATEGIES ARE PREDOMINANTLY AIMED AT SUPPRESSING IMMUNE ACTIVATION AND PRO-INFLAMMATORY EFFECTOR MECHANISMS, IGNORING THE OPPORTUNITY TO ALSO PROMOTE TOLERANCE BY BOOSTING THE REGULATORY SIDE OF THE IMMUNE BALANCE. HISTONE DEACETYLASES (HDACS) CAN DEACETYLATE BOTH HISTONE AND NON-HISTONE PROTEINS AND HAVE BEEN DEMONSTRATED TO MODULATE EPIGENETIC REGULATION AS WELL AS CELLULAR SIGNALING IN VARIOUS CELL TYPES. IMPORTANTLY, HDACS ARE POTENT REGULATORS OF BOTH TEFF CELL AND TREG CELL FUNCTION AND CAN THUS BE REGARDED AS ATTRACTIVE THERAPEUTIC TARGETS IN CHRONIC INFLAMMATORY ARTHRITIS. HDAC INHIBITORS (HDACI) HAVE PROVEN THERAPEUTIC POTENTIAL IN THE CANCER FIELD, AND ARE PRESENTLY BEING EXPLORED FOR THEIR POTENTIAL IN THE TREATMENT OF AUTOIMMUNE DISEASES. SPECIFIC HDACI HAVE ALREADY BEEN DEMONSTRATED TO REDUCE THE SECRETION OF PRO-INFLAMMATORY CYTOKINES BY TEFF CELLS, AND PROMOTE TREG NUMBERS AND SUPPRESSIVE CAPACITY IN VITRO AND IN VIVO. IN THIS REVIEW, WE OUTLINE THE ROLE OF THE DIFFERENT CLASSES OF HDACS IN BOTH TEFF CELL AND TREG CELL FUNCTION. FURTHERMORE, WE WILL REVIEW THE EFFECT OF DIFFERENT HDACI ON T CELL TOLERANCE AND EXPLORE THEIR POTENTIAL AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF OLIGOARTICULAR AND POLYARTICULAR JIA. 2019 19 198 32 ACQUIRED TRANSCRIPTIONAL PROGRAMMING IN FUNCTIONAL AND EXHAUSTED VIRUS-SPECIFIC CD8 T CELLS. PURPOSE OF REVIEW: FAILURE TO CONTROL VIRAL INFECTIONS SUCH AS HIV RESULTS IN T-CELL RECEPTOR (TCR) AND INHIBITORY RECEPTOR DRIVEN EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS. PERSISTENT SIGNALING BY THESE RECEPTORS DURING CHRONIC VIRAL INFECTION SCULPTS THE TRANSCRIPTIONAL REGULATORY PROGRAMS OF VIRUS-SPECIFIC T CELLS. THE RESULTING GENE EXPRESSION PROFILE IS TAILORED TO TEMPER THE POTENTIALLY DAMAGING EFFECTOR FUNCTIONS OF CYTOTOXIC T CELLS AND ADAPT THEM TO AN ANTIGEN-RICH AND INFLAMMATION-RICH ENVIRONMENT. HERE WE REVIEW RECENT STUDIES INVESTIGATING MECHANISMS OF TRANSCRIPTIONAL REGULATION OF EFFECTOR, FUNCTIONAL MEMORY, AND EXHAUSTED T-CELL FUNCTIONS DURING ACUTE VERSUS CHRONIC INFECTIONS. RECENT FINDINGS: PATTERNS OF GENE EXPRESSION IN VIRUS-SPECIFIC CD8 T CELLS ARE A RESULT OF A COMBINATION OF PRO AND INHIBITORY SIGNALS FROM ANTIGEN PRESENTATION (TCR-MEDIATED) AND CO-INHIBITORY RECEPTOR LIGATION (PD-1, 2B4). FURTHER, MEMORY-SPECIFIC TRANSCRIPTIONAL REGULATION OF 2B4 EXPRESSION AND SIGNALING IMPOSE A SELF-LIMITING SECONDARY EFFECTOR RESPONSE TO A PROLONGED VIRAL INFECTION. ADDITIONALLY, DIFFERENTIATION OF FUNCTIONAL MEMORY CD8 T CELLS IS COUPLED WITH ACQUISITION OF A REPRESSIVE EPIGENETIC PROGRAM FOR PD-1 EXPRESSION. HOWEVER, CHRONIC INFECTION PROVIDES A SIGNAL THAT BLOCKS THE ACQUISITION OF THESE EPIGENETIC MODIFICATIONS REINFORCING THE SUPPRESSION OF CYTOTOXIC LYMPHOCYTE (CTL) FUNCTIONS IN EXHAUSTED CELLS. SUMMARY: CURRENT FINDINGS SUGGEST THAT THE MECHANISM(S) THAT DELINEATE FUNCTIONAL MEMORY VERSUS EXHAUSTION ARE COUPLED WITH ACQUISITION OF TRANSCRIPTIONAL PROGRAMS AT THE EFFECTOR STAGE OF DIFFERENTIATION, REINFORCED BY CESSATION OR PERSISTENCE OF TCR SIGNALING. 2012 20 1966 32 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