1 5555 124 ROLE OF FLUORIDE INDUCED EPIGENETIC ALTERATIONS IN THE DEVELOPMENT OF SKELETAL FLUOROSIS. FLUORIDE IS AN ESSENTIAL TRACE ELEMENT REQUIRED FOR PROPER BONE AND TOOTH DEVELOPMENT. SYSTEMIC HIGH EXPOSURE TO FLUORIDE THROUGH ENVIRONMENTAL EXPOSURE (DRINKING WATER AND FOOD) MAY RESULT IN TOXICITY CAUSING A DISORDER CALLED FLUOROSIS. IN THE PRESENT STUDY, WE INVESTIGATED THE ALTERATION IN DNA METHYLATION PROFILE WITH CHRONIC EXPOSURE (30 DAYS) TO FLUORIDE (8 MG/L) AND ITS RELEVANCE IN THE DEVELOPMENT OF FLUOROSIS. WHOLE GENOME BISULFITE SEQUENCING (WGBS) WAS CARRIED OUT IN HUMAN OSTEOSARCOMA CELLS (HOS) EXPOSED TO FLUORIDE. WHOLE GENOME BISULFITE SEQUENCING (WGBS) AND FUNCTIONAL ANNOTATION OF DIFFERENTIALLY METHYLATED GENES INDICATE ALTERATIONS IN METHYLATION STATUS OF GENES INVOLVED IN BIOLOGICAL PROCESSES ASSOCIATED WITH BONE DEVELOPMENT PATHWAYS. COMBINED ANALYSIS OF PROMOTER DNA HYPER METHYLATION, STRING: FUNCTIONAL PROTEIN ASSOCIATION NETWORKS AND GENE EXPRESSION ANALYSIS REVEALED EPIGENETIC ALTERATIONS IN BMP1, METAP2, MMP11 AND BACH1 GENES, WHICH PLAYS A ROLE IN THE EXTRACELLULAR MATRIX DISASSEMBLY, COLLAGEN CATABOLIC/ORGANIZATION PROCESS, SKELETAL MORPHOGENESIS/DEVELOPMENT, OSSIFICATION AND OSTEOBLAST DEVELOPMENT. THE PRESENT STUDY SHOWS THAT FLUORIDE CAUSES PROMOTER DNA HYPERMETHYLATION IN BMP1, METAP2, MMP11 AND BACH1 GENES WITH SUBSEQUENT DOWN-REGULATION IN THEIR EXPRESSION LEVEL (RNA LEVEL). THE RESULTS IMPLIES THAT FLUORIDE INDUCED DNA HYPERMETHYLATION OF THESE GENES MAY HAMPER EXTRACELLULAR MATRIX DEPOSITION, CARTILAGE FORMATION, ANGIOGENESIS, VASCULAR SYSTEM DEVELOPMENT AND POROSITY OF BONE, THUS PROMOTE SKELETAL FLUOROSIS. 2019 2 5556 47 ROLE OF FLUORIDE INDUCED HISTONE TRIMETHYLATION IN DEVELOPMENT OF SKELETAL FLUOROSIS. CHRONIC EXPOSURE TO FLUORIDE HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF SKELETAL FLUOROSIS. LIMITED REPORTS ARE AVAILABLE ON FLUORIDE INDUCED HISTONE MODIFICATION. HOWEVER, THE ROLE OF HISTONE MODIFICATION IN THE PATHOGENESIS OF SKELETAL FLUOROSIS IS NOT INVESTIGATED. IN THE PRESENT STUDY, WE HAVE INVESTIGATED THE ROLE OF FLUORIDE INDUCED HISTONE MODIFICATION ON FLUOROSIS DEVELOPMENT USING HUMAN OSTEOSARCOMA (HOS) CELL LINE. THE EXPRESSION OF HISTONE METHYLTRANSFERASES (EHMT1 AND EHZ2) AND LEVEL OF GLOBAL HISTONE TRIMETHYLATION (H3K9 AND H3K27) HAVE BEEN ASSESSED AND OBSERVED TO BE INCREASED SIGNIFICANTLY AFTER FLUORIDE EXPOSURE (8 MG/L). EPITECT CHROMATIN IMMUNOPRECIPITATION (CHIP) QPCR ARRAY (HUMAN TGFBETA/BMP SIGNALING PATHWAY) WAS PERFORMED TO ASSESS THE H3K9 TRIMETHYLATION AT PROMOTER REGIONS OF PATHWAY-SPECIFIC GENES. H3K9 CHIP PCR ARRAY ANALYSIS IDENTIFIED HYPER H3K9 TRIMETHYLATION IN PROMOTER REGIONS OF TGFBR2 AND SMAD3. QPCR AND STRING ANALYSIS WAS CARRIED OUT TO DETERMINE THE REPRESSIVE EPIGENETIC EFFECT OF H3K9 TRIMETHYLATION ON EXPRESSION PATTERN AND FUNCTIONAL ASSOCIATION OF IDENTIFIED GENES. IDENTIFIED GENES (TGFBR2 AND SMAD3) SHOWED DOWN-REGULATION WHICH CONFIRMS THE REPRESSIVE EPIGENETIC EFFECT OF PROMOTER H3K9 HYPER TRIMETHYLATION. EXPRESSION OF TWO OTHER VITAL GENES COL1A1 AND MMP13 INVOLVED IN TGFBR2-SMAD SIGNALING PATHWAY WAS ALSO FOUND TO BE DOWN-REGULATED WITH A DECREASE IN EXPRESSION OF TGFBR2 AND SMAD3. STRING ANALYSIS REVEALED FUNCTIONAL ASSOCIATION AND INVOLVEMENT OF IDENTIFIED GENES TGFBR2, SMAD3, COL1A1 AND MMP13 IN THE COLLAGEN AND CARTILAGE DEVELOPMENT/MORPHOGENESIS, CONNECTIVE TISSUE FORMATION, BIO-MINERAL TISSUE DEVELOPMENT, ENDOCHONDRAL BONE FORMATION, BONE AND SKELETAL MORPHOGENESIS. IN CONCLUSION, PRESENT INVESTIGATION IS A FIRST ATTEMPT TO LINK FLUORIDE INDUCED HYPER H3K9 TRI-METHYLATION MEDIATED REPRESSION OF TGFBR2 AND SMAD3 WITH THE DEVELOPMENT OF SKELETAL FLUOROSIS. 2018 3 3876 23 KDM4A-MEDIATED HISTONE DEMETHYLATION OF SLC7A11 INHIBITS CELL FERROPTOSIS IN OSTEOSARCOMA. OSTEOSARCOMA (OS) IS THE MOST COMMON TYPE OF BONE TUMOR THAT SERIOUSLY AFFECTS LIMB FUNCTION AND INDUCES GREAT PAIN IN PATIENTS. LUNG METASTASIS AND CHEMOTHERAPY RESISTANCE ARE TWO KEY ISSUES LEADING TO THE POOR PROGNOSIS OF OS PATIENTS, THEREFORE NEW TREATMENT TARGETS AND STRATEGIES ARE URGENTLY NEEDED. IN OUR STUDY, WE UNCOVERED THE ROLE OF HISTONE DEMETHYLASE KDM4A IN REGULATING OS CELL FERROPTOSIS AND TUMOR PROGRESSION. KDM4A WAS SIGNIFICANTLY UPREGULATED IN OS SPECIMENS AND HIGH KDM4A EXPRESSION WAS ASSOCIATED WITH POORER PROGNOSIS IN OS PATIENTS. OUR DATA INDICATED THAT TARGETING KDM4A SIGNIFICANTLY INCREASED OS CELL DEATH, ENHANCED CISPLATIN RESPONSE, AND ATTENUATED MIGRATION ABILITY IN VITRO. KDM4A DEPLETION DRAMATICALLY INHIBITED TUMOR PROGRESSION AND LUNG METASTASIS OF OS IN VIVO FURTHER EXPERIMENTS CONFIRMED THAT KDM4A KNOCKDOWN PROMOTED OS CELL FERROPTOSIS, A SPECIAL NON-APOPTOTIC FORM OF CELL DEATH. KDM4A REGULATES SLC7A11 TRANSCRIPTION AND OS CELL FERROPTOSIS BY CONTROLLING H3K9ME3 DEMETHYLATION IN THE PROMOTER REGION OF SLC7A11. OUR FINDINGS DEEPENED THE RECOGNITION OF EPIGENETIC REGULATORY MECHANISM IN OS TUMORIGENESIS, CHEMORESISTANCE, AND METASTASIS, SUGGESTING THAT KDM4A ACTIVITY MAY BE A POTENTIAL THERAPEUTIC TARGET FOR FUTURE OS TREATMENT. 2021 4 6105 29 THE EMERGING ROLE OF LNCRNA FENDRR IN MULTIPLE CANCERS: A REVIEW. LONG NONCODING RNAS (LNCRNAS) ARE PROMINENT AS CRUCIAL REGULATORS OF TUMOR ESTABLISHMENT AND ARE REPEATEDLY DYSREGULATED IN MULTIPLE CANCERS. THEREFORE, LNCRNAS HAVE BEEN IDENTIFIED TO PLAY AN ESSENTIAL FUNCTION IN CARCINOGENESIS AND PROGRESSION OF CANCER AT GENETIC AND EPIGENETIC LEVELS. FENDRR (FETAL-LETHAL NONCODING DEVELOPMENTAL REGULATORY RNA) AS A LNCRNA IS A HALLMARK OF VARIOUS MALIGNANCIES. FENDRR IS CRUCIAL FOR MULTIPLE ORGANS' DEVELOPMENT, SUCH AS THE LUNG AND HEART. THE EFFECTS OF FENDRR UNDER SIGNALING PATHWAYS IN DIFFERENT CANCERS HAVE BEEN IDENTIFIED. IN ADDITION, IT HAS BEEN VERIFIED THAT FENDRR CAN AFFECT THE DEVELOPMENT AND PROGRESSION OF VARIOUS CANCERS. IN ADDITION, FENDRR EXPRESSION HAS BEEN ASSOCIATED WITH EPIGENETIC REGULATION OF TARGET GENES PARTICIPATING IN TUMOR IMMUNITY. FURTHERMORE, FENDRR DOWNREGULATION WAS OBSERVED IN VARIOUS TYPES OF CANCERS, INCLUDING COLORECTAL CANCER, GASTRIC CANCER, PANCREATIC CANCER, CHOLANGIOCARCINOMA, LIVER CANCER, GALLBLADDER CANCER, LUNG CANCER, BREAST CANCER, ENDOMETRIAL CANCER, PROSTATE CANCER, CHRONIC MYELOID LEUKEMIA, OSTEOSARCOMA, AND CUTANEOUS MALIGNANT MELANOMA CELLS. HERE, WE REVIEW THE BIOLOGICAL FUNCTIONS AND MOLECULAR MECHANISMS OF FENDRR IN SEVERAL CANCERS, AND WE WILL DISCUSS ITS POTENTIAL AS A CANCER BIOMARKER AND AS A PROBABLE OPTION FOR CANCER TREATMENT. 2023 5 1484 27 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS. 2021 6 4703 20 NIK AS A DRUGGABLE MEDIATOR OF TISSUE INJURY. NF-KAPPAB-INDUCING KINASE (NIK, MAP3K14) IS BEST KNOWN AS THE APICAL KINASE THAT TRIGGERS NON-CANONICAL NF-KAPPAB ACTIVATION AND BY ITS ROLE IN THE IMMUNE SYSTEM. RECENT DATA INDICATE A ROLE FOR NIK EXPRESSED BY NON-LYMPHOID CELLS IN CANCER, KIDNEY DISEASE, LIVER INJURY, GLUCOSE HOMEOSTASIS, OSTEOSARCOPENIA, VASCULAR CALCIFICATION, HEMATOPOIESIS, AND ENDOTHELIAL FUNCTION. THE SPECTRUM OF NIK-ASSOCIATED DISEASE NOW RANGES FROM IMMUNODEFICIENCY (WHEN NIK IS DEFECTIVE) TO AUTOIMMUNITY, CANCER, STERILE INFLAMMATION, FIBROSIS, AND METABOLIC DISEASE WHEN NIK IS OVERACTIVE. THE DEVELOPMENT OF NOVEL SMALL-MOLECULE NIK INHIBITORS HAS PAVED THE WAY TO TEST NIK TARGETING TO TREAT DISEASE IN VIVO, AND MAY EVENTUALLY LEAD TO NIK TARGETING IN THE CLINIC. IN ADDITION, NIK ACTIVATORS ARE BEING EXPLORED FOR SPECIFIC CONDITIONS SUCH AS MYELOID LEUKEMIA. 2019 7 122 27 A SYSTEMATIC REVIEW ON FLUORIDE-INDUCED EPIGENETIC TOXICITY IN MAMMALS. FLUORIDE, ONE OF THE GLOBAL GROUNDWATER CONTAMINANTS, IS UBIQUITOUS IN OUR DAY-TO-DAY LIFE FROM VARIOUS NATURAL AND ANTHROPOGENIC SOURCES. NUMEROUS IN VITRO, IN VIVO, AND EPIDEMIOLOGICAL STUDIES ARE CONDUCTED TO UNDERSTAND THE EFFECT OF FLUORIDE ON BIOLOGICAL SYSTEMS. A LOW CONCENTRATION OF FLUORIDE IS REPORTED TO INCREASE ORAL HEALTH, WHEREAS CHRONIC EXPOSURE TO HIGHER CONCENTRATIONS CAUSES FLUORIDE TOXICITY (FLUOROSIS). IT INCLUDES DENTAL FLUOROSIS, SKELETAL FLUOROSIS, AND FLUORIDE TOXICITY IN SOFT TISSUES. THE MECHANISM OF FLUORIDE TOXICITY HAS BEEN REVIEWED EXTENSIVELY. HOWEVER, EPIGENETIC REGULATION IN FLUORIDE TOXICITY HAS NOT BEEN REVIEWED. THIS SYSTEMATIC REVIEW SUMMARIZES THE CURRENT KNOWLEDGE REGARDING FLUORIDE-INDUCED EPIGENETIC TOXICITY IN THE IN VITRO, IN VIVO, AND EPIDEMIOLOGICAL STUDIES IN MAMMALIAN SYSTEMS. WE EXAMINED FOUR DATABASES FOR THE ASSOCIATION BETWEEN EPIGENETICS AND FLUORIDE EXPOSURE. OUT OF 932 ARTICLES (AS OF 31 MARCH 2022), 39 MET OUR INCLUSION CRITERIA. MOST OF THE STUDIES FOCUSED ON DIFFERENT GENES, AND OVERALL, PRELIMINARY EVIDENCE FOR EPIGENETIC REGULATION OF FLUORIDE TOXICITY WAS IDENTIFIED. WE FURTHER HIGHLIGHT THE NEED FOR EPIGENOME STUDIES RATHER THAN CANDIDATE GENES AND PROVIDE RECOMMENDATIONS FOR FUTURE RESEARCH. OUR RESULTS INDICATE A CORRELATION BETWEEN FLUORIDE EXPOSURE AND EPIGENETIC PROCESSES. FURTHER STUDIES ARE WARRANTED TO ELUCIDATE AND CONFIRM THE MECHANISM OF EPIGENETIC ALTERATIONS MEDIATED FLUORIDE TOXICITY. 2022 8 908 43 CHRONIC EXPOSURE TO ENVIRONMENTALLY RELEVANT CONCENTRATION OF FLUORIDE IMPAIRS OSTEOBLAST'S COLLAGEN SYNTHESIS AND MATRIX MINERALIZATION: INVOLVEMENT OF EPIGENETIC REGULATION IN SKELETAL FLUOROSIS. GLOBALLY, 200 MILLION PEOPLE ARE SUFFERING FROM TOXIC MANIFESTATIONS OF FLUORIDE(F), DENTAL AND SKELETAL FLUOROSIS; UNFORTUNATELY, THERE IS NO TREATMENT. TO UNRAVEL THE PATHOGENESIS OF SKELETAL FLUOROSIS, WE ESTABLISHED FLUOROSIS MICE BY TREATING ENVIRONMENTALLY RELEVANT CONCENTRATION OF F (15 PPM NAF) THROUGH DRINKING WATER FOR 4 MONTHS. AS IN SKELETAL FLUOROSIS, LOCOMOTOR DISABILITY, CRIPPLING DEFORMITIES OCCUR AND THUS, OUR HYPOTHESIS WAS F MIGHT ADVERSELY AFFECTS COLLAGEN WHICH GIVES THE BONE TENSILE STRENGTH. THIS WORK INEVITABLY HAD TO BE CARRIED OUT ON OSTEOBLAST CELLS, RESPONSIBLE FOR SYNTHESIS, DEPOSITION, AND MINERALIZATION OF BONE MATRIX. ISOLATED OSTEOBLAST CELLS WERE CONFIRMED BY ALP ACTIVITY AND MINERALIZED NODULES FORMATION. EXPRESSION OF COLLAGEN COL1A1, COL1A2, COL1A1 WAS SIGNIFICANTLY REDUCED IN TREATED MICE. FURTHER, A STUDY REVEALED THE INVOLVEMENT OF EPIGENETIC REGULATION BY PROMOTER HYPERMETHYLATION OF COL1A1; EXPRESSIONAL ALTERATIONS OF TRANSCRIPTION FACTORS, CALCIUM CHANNELS AND OTHER GENES E.G., CBFA-1, TGF-BETA1, BMP1, SP1, SP7, NF-(K)B P65, BMP-2, BGLAP, GPRC6A AND CAV(1.2) ARE ASSOCIATED WITH IMPAIRMENT OF COLLAGEN SYNTHESIS, DEPOSITION AND DECREASED MINERALIZATION THUS, ENFEEBLING BONE HEALTH. THIS STUDY INDICATES THE POSSIBLE ASSOCIATION OF EPIGENETIC REGULATION IN SKELETAL FLUOROSIS. HOWEVER, NO ASSOCIATION WAS FOUND BETWEEN POLYMORPHISMS IN THE COL1A1 (RSAI, HINDIII) AND COL1A2 (RSAI, HINDIII) GENES WITH FLUOROSIS IN MICE. 2023 9 6470 24 TLR7 AND TLR8 EXPRESSION INCREASES TUMOR CELL PROLIFERATION AND PROMOTES CHEMORESISTANCE IN HUMAN PANCREATIC CANCER. CHRONIC INFLAMMATION AS AN IMPORTANT EPIGENETIC AND ENVIRONMENTAL FACTOR FOR PUTATIVE TUMORIGENESIS AND TUMOR PROGRESSION MAY BE ASSOCIATED WITH SPECIFIC ACTIVATION OF TOLL-LIKE RECEPTORS (TLR). RECENTLY, CARCINOGENESIS HAS BEEN SUGGESTED TO BE DEPENDENT ON TLR7 SIGNALING. IN THE PRESENT STUDY, WE DETERMINED THE ROLE OF BOTH TLR7 AND TLR8 EXPRESSION AND SIGNALING IN TUMOR CELL PROLIFERATION AND CHEMORESISTANCE IN PANCREATIC CANCER. EXPRESSION OF TLR7/TLR8 IN UICC STAGE I-IV PANCREATIC CANCER, CHRONIC PANCREATITIS, NORMAL PANCREATIC TISSUE AND HUMAN PANCREATIC (PANC1) CANCER CELL LINE WAS EXAMINED. FOR IN VITRO/IN VIVO STUDIES TLR7/TLR8 OVEREXPRESSING PANC1 CELL LINES WERE GENERATED AND ANALYZED FOR EFFECTS OF (UN-)STIMULATED TLR EXPRESSION ON TUMOR CELL PROLIFERATION AND CHEMORESISTANCE. TLR EXPRESSION WAS INCREASED IN PANCREATIC CANCER, WITH STAGE-DEPENDENT UPREGULATION IN ADVANCED TUMORS, COMPARED TO EARLIER STAGES AND CHRONIC PANCREATITIS. STIMULATION OF TLR7/TLR8 OVEREXPRESSING PANC1 CELLS RESULTED IN ELEVATED NF-KAPPAB AND COX-2 EXPRESSION, INCREASED CANCER CELL PROLIFERATION AND REDUCED CHEMOSENSITIVITY. MORE IMPORTANTLY, TLR7/TLR8 EXPRESSION INCREASED TUMOR GROWTH IN VIVO. OUR DATA DEMONSTRATE A STAGE-DEPENDENT UPREGULATION OF BOTH TLR7 AND TLR8 EXPRESSION IN PANCREATIC CANCER. FUNCTIONAL ANALYSIS IN HUMAN PANCREATIC CANCER CELLS POINT TO A SIGNIFICANT ROLE OF BOTH TLRS IN CHRONIC INFLAMMATION-MEDIATED TLR7/TLR8 SIGNALING LEADING TO TUMOR CELL PROLIFERATION AND CHEMORESISTANCE. 2015 10 767 23 CD24 MEDIATES GASTRIC CARCINOGENESIS AND PROMOTES GASTRIC CANCER PROGRESSION VIA STAT3 ACTIVATION. THE DEVELOPMENT OF GASTRIC CANCER (GC) IS A COMPLEX MULTISTEP PROCESS, INCLUDING NUMEROUS GENETIC AND EPIGENETIC CHANGES. CD24 IS ASSOCIATED WITH ENHANCED INVASIVENESS OF GC AND A POOR PROGNOSIS. HOWEVER, THE MECHANISM BY WHICH CD24 INDUCES GC PROGRESSION REMAINS POORLY CHARACTERIZED. HERE, WE FOUND THAT THE EXPRESSION OF CD24 GRADUALLY INCREASED IN SAMPLES OF NORMAL GASTRIC MUCOSA, NON-ATROPHIC CHRONIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS (CAG), CAG WITH INTESTINAL METAPLASIA, DYSPLASIA AND GC. MOREOVER, THE KNOCKDOWN OF CD24 INDUCED SIGNIFICANT LEVELS OF APOPTOSIS IN GC CELLS VIA THE MITOCHONDRIAL APOPTOTIC PATHWAY. CD24 MAY ALSO PROMOTE CELLULAR INVASION AND REGULATE THE EXPRESSION OF E-CADHERIN, FIBRONECTIN AND VITAMIN D RECEPTOR IN GC CELLS. THE ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) MAY MEDIATE CD24-INDUCED GC SURVIVAL AND INVASION IN VITRO. FURTHERMORE, CD24-INDUCED GC PROGRESSION AND STAT3 ACTIVATION COULD ALSO BE DETECTED IN VIVO AND IN CLINICAL GC TISSUES SAMPLES. TAKEN TOGETHER, OUR RESULTS INDICATE THAT CD24 MEDIATES GASTRIC CARCINOGENESIS AND MAY PROMOTE GC PROGRESSION BY SUPPRESSING APOPTOSIS AND PROMOTING INVASION, WITH THE ACTIVATION OF STAT3 PLAYING A CRITICAL ROLE. 2014 11 4033 27 M6A HYPOMETHYLATION OF DNMT3B REGULATED BY ALKBH5 PROMOTES INTERVERTEBRAL DISC DEGENERATION VIA E4F1 DEFICIENCY. BACKGROUND: THE INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH ACCOUNTS FOR A MAIN CAUSE OF DISABILITY. N6-METHYLADENOSINE (M6A) IS THE MOST ABUNDANT INTERNAL MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS INVOLVED IN VARIOUS DISEASES AND CELLULAR PROCESSES BY MODULATING MRNA FATE. HOWEVER, THE CRITICAL ROLE OF M6A REGULATION IN IVD DEGENERATION REMAINS UNCLEAR. NUCLEUS PULPOSUS CELL (NPC) SENESCENCE IS CRITICAL FOR THE PROGRESSION OF IVD DEGENERATION. HERE, WE UNCOVERED THE ROLE AND EXPLORED THE REGULATORY MECHANISM OF M6A IN NPC SENESCENCE DURING IVD DEGENERATION. METHODS: IDENTIFICATION OF NPC SENESCENCE DURING IVD DEGENERATION WAS BASED ON THE ANALYSIS OF TISSUE SAMPLES AND THE CELLULAR MODEL. ALKBH5 UPREGULATION INDUCING CELLULAR SENESCENCE WAS CONFIRMED BY FUNCTIONAL EXPERIMENTS IN VIVO AND IN VITRO. CHIP-QPCR AND DNA-PULLDOWN WERE USED TO REVEAL INCREASED ALKBH5 WAS REGULATED BY KDM4A-MEDIATED H3K9ME3. FURTHERMORE, ME-RIP-SEQ WAS PERFORMED TO IDENTIFY M6A HYPOMETHYLATION OF DNMT3B TRANSCRIPTS IN SENESCENT NPCS. STABILITY ANALYSIS SHOWED THAT DNMT3B EXPRESSION WAS ENHANCED FOR LESS YTHDF2 RECOGNITION AND INCREASED DNMT3B PROMOTED NPC SENESCENCE AND IVD DEGENERATION VIA E4F1 METHYLATION BY IN VIVO AND IN VITRO ANALYSES. RESULTS: EXPRESSION OF ALKBH5 IS ENHANCED DURING IVD DEGENERATION AND NPC SENESCENCE, DUE TO DECREASED KDM4A-MEDIATED H3K9ME3 MODIFICATION. FUNCTIONALLY, ALKBH5 CAUSES NPC SENESCENCE BY DEMETHYLATING DNMT3B TRANSCRIPTS AND IN TURN PROMOTING ITS EXPRESSION VIA LESS YTHDF2 RECOGNITION AND FOLLOWING DEGRADATION DUE TO TRANSCRIPT HYPOMETHYLATION IN VITRO AND IN VIVO. INCREASED DNMT3B PROMOTES THE DEVELOPMENT OF IVD DEGENERATION AND NPC SENESCENCE, MECHANISTICALLY BY METHYLATING CPG ISLANDS OF E4F1 AT THE PROMOTER REGION AND THUS RESTRAINING ITS TRANSCRIPTION AND EXPRESSION. CONCLUSIONS: COLLECTIVELY, OUR FINDINGS REVEAL AN EPIGENETIC INTERPLAY MECHANISM IN NPC SENESCENCE AND IVD DEGENERATION, PRESENTING A CRITICAL PRO-SENESCENCE ROLE OF ALKBH5 AND M6A HYPOMETHYLATION, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF TARGETING THE M6A/DNMT3B/E4F1 AXIS FOR TREATING IVD DEGENERATION. 2022 12 6455 26 THYMOQUINONE ENHANCES APOPTOSIS OF K562 CHRONIC MYELOID LEUKEMIA CELLS THROUGH HYPOMETHYLATION OF SHP-1 AND INHIBITION OF JAK/STAT SIGNALING PATHWAY. THE EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES (TSGS) IS CRITICAL IN THE DEVELOPMENT OF CHRONIC MYELOID LEUKEMIA (CML). SHP-1 FUNCTIONS AS A TSG AND NEGATIVELY REGULATES JAK/STAT SIGNALING. ENHANCEMENT OF SHP-1 EXPRESSION BY DEMETHYLATION PROVIDES MOLECULAR TARGETS FOR THE TREATMENT OF VARIOUS CANCERS. THYMOQUINONE (TQ), A CONSTITUENT OF NIGELLA SATIVA SEEDS, HAS SHOWN ANTI-CANCER ACTIVITIES IN VARIOUS CANCERS. HOWEVER, TQS EFFECT ON METHYLATION IS NOT FULLY CLEAR. THEREFORE, THE AIM OF THIS STUDY IS TO ASSESS TQS ABILITY TO ENHANCE THE EXPRESSION OF SHP-1 THROUGH MODIFYING DNA METHYLATION IN K562 CML CELLS. THE ACTIVITIES OF TQ ON CELL CYCLE PROGRESSION AND APOPTOSIS WERE EVALUATED USING A FLUOROMETRIC-RED CELL CYCLE ASSAY AND ANNEXIN V-FITC/PI, RESPECTIVELY. THE METHYLATION STATUS OF SHP-1 WAS STUDIED BY PYROSEQUENCING ANALYSIS. THE EXPRESSION OF SHP-1, TET2, WT1, DNMT1, DNMT3A, AND DNMT3B WAS DETERMINED USING RT-QPCR. THE PROTEIN PHOSPHORYLATION OF STAT3, STAT5, AND JAK2 WAS ASSESSED USING JESS WESTERN ANALYSIS. TQ SIGNIFICANTLY DOWNREGULATED THE DNMT1 GENE, DNMT3A GENE, AND DNMT3B GENE AND UPREGULATED THE WT1 GENE AND TET2 GENE. THIS LED TO HYPOMETHYLATION AND RESTORATION OF SHP-1 EXPRESSION, RESULTING IN INHIBITION OF JAK/STAT SIGNALING, INDUCTION OF APOPTOSIS, AND CELL CYCLE ARREST. THE OBSERVED FINDINGS IMPLY THAT TQ PROMOTES APOPTOSIS AND CELL CYCLE ARREST IN CML CELLS BY INHIBITING JAK/STAT SIGNALING VIA RESTORATION OF THE EXPRESSION OF JAK/STAT-NEGATIVE REGULATOR GENES. 2023 13 6134 20 THE EPIGENETICALLY-REGULATED MIR-34A TARGETING C-SRC SUPPRESSES RAF/MEK/ERK SIGNALING PATHWAY IN K-562 CELLS. PREVIOUS REPORTS SHOW THAT MIR-34A SUPPRESSED K-562 CELL PROLIFERATION AND CONTRIBUTED TO MEGAKARYOCYTIC DIFFERENTIATION OF K-562 CELLS. HERE, WE REPORTED THAT MIR-34A, A TUMOR SUPPRESSOR GENE, IS DOWN-REGULATED IN THE K-562 CELLS AND CHRONIC MYELOID LEUKEMIA (CML) PATIENTS DUE TO ABERRANT DNA HYPERMETHYLATION. C-SRC IS A TARGET OF MIR-34A. RESTORING MIR-34A EXPRESSION RESULTED IN DOWN-REGULATION OF C-SRC AND PHOSPHORYLATED (TYR416) C-SRC PROTEIN IN K-562 CELLS, WHICH CONSEQUENTLY TRIGGERED SUPPRESSION OF THE RAF/MEK/ERK SIGNALING PATHWAY TO DECREASE CELL PROLIFERATION. 2017 14 3389 43 HOMOCYSTEINE SUPPRESSES THE EXPRESSION OF THE COLLAGEN CROSS-LINKER LYSYL OXIDASE INVOLVING IL-6, FLI1, AND EPIGENETIC DNA METHYLATION. ELEVATED HOMOCYSTEINE (HCYS) SERUM LEVELS REPRESENT A RISK FACTOR FOR SEVERAL CHRONIC PATHOLOGIES, INCLUDING CARDIOVASCULAR DISEASE, ATHEROSCLEROSIS, AND CHRONIC RENAL FAILURE, AND AFFECT BONE DEVELOPMENT, QUALITY, AND HOMEOSTASIS. HCYS INFLUENCES THE FORMATION OF A STABLE BONE MATRIX DIRECTLY THROUGH THE INHIBITION OF THE COLLAGEN CROSS-LINKING ENZYME LYSYL OXIDASE (LOX) AND, AS WE HAVE SHOWN RECENTLY, BY REPRESSING ITS MRNA EXPRESSION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE MECHANISMS INVOLVED IN THIS PROCESS. THROUGH EVALUATION OF GENE ARRAYS, QUANTITATIVE RT-PCR, IMMUNOBLOTS, AND ELISA, WE IDENTIFIED A HCYS-DEPENDENT STIMULATION OF INTERLEUKIN 6 (IL-6) AND GENES INVOLVED IN IL-6/JANUS KINASE 2 (JAK2)-DEPENDENT SIGNAL TRANSDUCTION PATHWAYS IN PRE-OSTEOBLASTIC MC3T3-E1 CELLS. MOREOVER, UP-REGULATION OF GENES ESSENTIAL FOR EPIGENETIC DNA METHYLATION (DNA (CYTOSINE-5)-METHYLTRANSFERASES AND HELICASE LYMPHOID-SPECIFIC (HELLS) WAS OBSERVED. FURTHER INVESTIGATIONS DEMONSTRATED THAT HCYS INCREASED VIA IL-6/JAK2 THE EXPRESSION OF FLI1 (FRIEND LEUKEMIA VIRUS INTEGRATION 1), A TRANSCRIPTION FACTOR, WHICH WE FOUND ESSENTIAL FOR IL-6-DEPENDENT DNMT1 STIMULATION. CPG METHYLATION ANALYSIS OF CPG-RICH LOX PROXIMAL PROMOTER REVEALED AN INCREASED CPG METHYLATION STATUS AFTER TREATMENT OF THE CELLS WITH HCYS INDICATING AN EPIGENETIC ORIGIN FOR HCYS-DEPENDENT LOX REPRESSION. INHIBITION OF THE IL-6/JAK2 PATHWAY OR OF CPG METHYLATION REVERSED THE REPRESSIVE EFFECT OF HCYS ON LOX EXPRESSION. IN CONCLUSION, WE DEMONSTRATE THAT HCYS STIMULATES IL-6 SYNTHESIS IN OSTEOBLASTS, WHICH IS KNOWN TO AFFECT BONE METABOLISM VIA OSTEOCLASTS. FURTHERMORE, IL-6 STIMULATION RESULTS VIA JAK2, FLI1, AND DNMT1 IN DOWN-REGULATION OF LOX EXPRESSION BY EPIGENETIC CPG METHYLATION REVEALING A NEW MECHANISM NEGATIVELY AFFECTING BONE MATRIX FORMATION. 2011 15 6593 24 TUMOR-ASSOCIATED MACROPHAGES PROMOTE EPIGENETIC SILENCING OF GELSOLIN THROUGH DNA METHYLTRANSFERASE 1 IN GASTRIC CANCER CELLS. EPIGENETIC REPRESSION OF THE TUMOR SUPPRESSOR GELSOLIN (GSN) IS FREQUENTLY OBSERVED IN CANCERS. CHRONIC INFLAMMATION CAN PROMOTE TUMOR PROGRESSION VIA ABERRANT DNA METHYLATION. IN THIS STUDY, WE INVESTIGATED THE ROLE OF TUMOR-ASSOCIATED MACROPHAGES (TAMS) IN DNA METHYLATION OF THE GSN GENE DURING GASTRIC CANCER PROGRESSION. IMMUNOFLUORESCENCE STAINING OF 121 GASTRIC CANCER TISSUES SHOWED ABERRANT LOCALIZATION OF GSN AND DNA METHYLTRANSFERASE 1 (DNMT1) AND JUXTAPOSITION OF DNMT1 AND M2 TAMS. DECREASED GSN PROTEIN AND MRNA EXPRESSION AND INCREASED DNA METHYLATION IN THE GSN PROMOTER WERE OBSERVED IN GASTRIC CANCER CELL LINES AND CLINICAL SPECIMENS. TO EXAMINE THE EFFECT OF TAMS ON DNA METHYLATION IN GASTRIC CANCER CELLS, WE PERFORMED IN VITRO COCULTURE ASSAYS AND FOUND INCREASED DNMT1 EXPRESSION BUT DECREASED GSN EXPRESSION IN GASTRIC CANCER CELLS AFTER COCULTURE WITH U937 CELLS. KNOCKDOWN OF DNMT1 EXPRESSION IN GASTRIC CANCER CELLS COULD ABORT U937 COCULTURE-MEDIATED GSN DOWNREGULATION. MEANWHILE, CCL5 WAS THE MAIN CHEMOKINE UPREGULATED IN COCULTURE MEDIUM. TREATMENT WITH CCL5 COULD INDUCE DNMT1 EXPRESSION IN GASTRIC CANCER CELLS VIA STAT3 SIGNALING. INHIBITING DNMT1 ACTIVITY WITH PROCAINAMIDE, INHIBITING DNA METHYLATION WITH 5-AZA, OR INHIBITING CCL5/CCR5 SIGNALING WITH MARAVIROC REDUCED TUMOR GROWTH IN VIVO IN CONCLUSION, UPREGULATION OF DNMT1 BY CCL5/CCR5/STAT3 SIGNALING IS CRITICAL FOR TAM-MEDIATED GSN SILENCING IN GASTRIC CANCER. THIS STUDY IDENTIFIED POTENTIAL TARGETS FOR GASTRIC CANCER THERAPY. CANCER IMMUNOL RES; 5(10); 885-97. (C)2017 AACR. 2017 16 2441 24 EPIGENETIC SILENCING OF TUMOR SUPPRESSOR MIR-3151 CONTRIBUTES TO CHINESE CHRONIC LYMPHOCYTIC LEUKEMIA BY CONSTITUTIVE ACTIVATION OF MADD/ERK AND PIK3R2/AKT SIGNALING PATHWAYS. WE HYPOTHESIZE THAT MIR-3151, LOCALIZED TO A GWAS-IDENTIFIED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) RISK LOCUS (8Q22.3), IS A TUMOR SUPPRESSOR MIRNA SILENCED BY PROMOTER DNA METHYLATION IN CLL. THE PROMOTER OF MIR-3151 WAS METHYLATED IN 5/7 (71%) CLL CELL LINES, 30/98 (31%) DIAGNOSTIC PRIMARY SAMPLES, BUT NOT NORMAL CONTROLS. METHYLATION OF MIR-3151 CORRELATED INVERSELY WITH EXPRESSION. TREATMENT WITH 5-AZA-2'-DEOXYCYTIDINE LED TO PROMOTER DEMETHYLATION AND MIR-3151 RE-EXPRESSION. LUCIFERASE ASSAY CONFIRMED MAP-KINASE ACTIVATING DEATH DOMAIN (MADD) AND PHOSPHOINOSITIDE-3-KINASE, REGULATORY SUBUNIT 2 (PIK3R2) AS DIRECT TARGETS OF MIR-3151. MOREOVER, RESTORATION OF MIR-3151 RESULTED IN INHIBITION OF CELLULAR PROLIFERATION AND ENHANCED APOPTOSIS, REPRESSION OF MADD AND PIK3R2, DOWNREGULATION OF MEK/ERK AND PI3K/AKT SIGNALING, AND REPRESSION OF MCL1. LASTLY, MIR-3151 METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH METHYLATION OF MIR-203 AND MIR-34B/C IN PRIMARY CLL SAMPLES. THEREFORE, THIS STUDY SHOWED THAT MIR-3151 IS A TUMOR SUPPRESSIVE MIRNA FREQUENTLY HYPERMETHYLATED AND HENCE SILENCED IN CLL. MIR-3151 SILENCING BY DNA METHYLATION PROTECTED CLL CELLS FROM APOPTOSIS THROUGH OVER-EXPRESSION OF ITS DIRECT TARGETS MADD AND PIK3R2, HENCE CONSTITUTIVE ACTIVATION OF MEK/ERK AND PI3K/AKT SIGNALING RESPECTIVELY, AND CONSEQUENTLY OVER-EXPRESSION OF MCL1. 2015 17 1022 33 CIRCULAR RNA HSA_CIRC_0098181 INHIBITS METASTASIS IN HEPATOCELLULAR CARCINOMA BY ACTIVATING THE HIPPO SIGNALING PATHWAY VIA INTERACTION WITH EEF2. INTRODUCTION AND OBJECTIVES: THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTI-STEP PROCESS THAT ACCUMULATES GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING CHANGES IN CIRCULAR RNA (CIRCRNA). THIS STUDY AIMED TO UNDERSTAND THE ALTERATIONS IN CIRCRNA EXPRESSION IN HCC DEVELOPMENT AND METASTASIS AND TO EXPLORE THE BIOLOGICAL FUNCTIONS OF CIRCRNA. MATERIALS AND METHODS: TEN PAIRS OF ADJACENT CHRONIC HEPATITIS TISSUES AND HCC TISSUES FROM PATIENTS WITHOUT VENOUS METASTASES, AND TEN HCC TISSUES FROM PATIENTS WITH VENOUS METASTASES WERE ANALYZED USING HUMAN CIRCRNA MICROARRAYS. DIFFERENTIALLY EXPRESSED CIRCRNAS WERE THEN VALIDATED BY QUANTITATIVE REAL-TIME PCR. IN VITRO AND IN VIVO ASSAYS WERE PERFORMED TO ASSESS THE ROLES OF THE CIRCRNA IN HCC PROGRESSION. RNA PULL-DOWN ASSAY, MASS SPECTROMETRY ANALYSIS, AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION WERE CONDUCTED TO EXPLORE THE PROTEIN PARTNERS OF THE CIRCRNA. RESULTS: CIRCRNA MICROARRAYS REVEALED THAT THE EXPRESSION PATTERNS OF CIRCRNAS ACROSS THE THREE GROUPS WERE SIGNIFICANTLY DIFFERENT. AMONG THESE, HSA_CIRC_0098181 WAS VALIDATED TO BE LOWLY EXPRESSED AND ASSOCIATED WITH POOR PROGNOSIS IN HCC PATIENTS. ECTOPIC EXPRESSION OF HSA_CIRC_0098181 DELAYED HCC METASTASIS IN VITRO AND IN VIVO. MECHANISTICALLY, HSA_CIRC_0098181 SEQUESTERED EUKARYOTIC TRANSLATION ELONGATION FACTOR 2 (EEF2) AND DISSOCIATED EEF2 FROM FILAMENTOUS ACTIN (F-ACTIN) TO PREVENT F-ACTIN FORMATION, WHICH BLOCKED ACTIVATION OF THE HIPPO SIGNALING PATHWAY. IN ADDITION, THE RNA BINDING PROTEIN QUAKING-5 BOUND DIRECTLY TO HSA_CIRC_0098181 AND INDUCED ITS BIOGENESIS. CONCLUSIONS: OUR STUDY REVEALS CHANGES IN CIRCRNA EXPRESSION FROM CHRONIC HEPATITIS, PRIMARY HCC, TO METASTATIC HCC. FURTHER, THE QKI5-HSA_CIRC_0098181-EEF2-HIPPO SIGNALING PATHWAY EXERTS A REGULATORY ROLE IN HCC. 2023 18 5064 27 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 19 3924 27 LIPOSOMAL UHRF1 SIRNA SHOWS LUNG FIBROSIS TREATMENT POTENTIAL THROUGH REGULATION OF FIBROBLAST ACTIVATION. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE INTERSTITIAL LUNG DISEASE ASSOCIATED WITH THE DECAY OF PULMONARY FUNCTION, WHICH LEADS TO A FATAL OUTCOME. AS AN ESSENTIAL EPIGENETIC REGULATOR OF DNA METHYLATION, THE INVOLVEMENT OF UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN FIBROBLAST ACTIVATION REMAINS LARGELY UNDEFINED IN PULMONARY FIBROSIS. IN THE PRESENT STUDY, WE FOUND THAT TGF-BETA1-MEDIATED UPREGULATION OF UHRF1 REPRESSED BECLIN 1 VIA METHYLATED INDUCTION OF ITS PROMOTER, WHICH FINALLY RESULTED IN FIBROBLAST ACTIVATION AND LUNG FIBROSIS BOTH IN VITRO AND IN VIVO. MOREOVER, KNOCKDOWN OF UHRF1 SIGNIFICANTLY ARRESTED FIBROBLAST PROLIFERATION AND REACTIVATED BECLIN 1 IN LUNG FIBROBLASTS. THUS, INTRAVENOUS ADMINISTRATION OF UHRF1 SIRNA-LOADED LIPOSOMES SIGNIFICANTLY PROTECTED MICE AGAINST EXPERIMENTAL PULMONARY FIBROSIS. ACCORDINGLY, OUR DATA SUGGEST THAT UHRF1 MIGHT BE A NOVEL POTENTIAL THERAPEUTIC TARGET IN THE PATHOGENESIS OF PULMONARY FIBROSIS. 2022 20 3944 33 LNCRNA H19-EZH2 INTERACTION PROMOTES LIVER FIBROSIS VIA REPROGRAMMING H3K27ME3 PROFILES. LIVER FIBROSIS IS A WOUND-HEALING PROCESS CHARACTERIZED BY EXCESS FORMATION OF EXTRACELLULAR MATRIX (ECM) FROM ACTIVATED HEPATIC STELLATE CELLS (HSCS). PREVIOUS STUDIES SHOW THAT BOTH EZH2, AN EPIGENETIC REGULATOR THAT CATALYZES LYSINE 27 TRIMETHYLATION ON HISTONE 3 (H3K27ME3), AND LONG NON-CODING RNA H19 ARE HIGHLY CORRELATED WITH FIBROGENESIS. IN THE CURRENT STUDY, WE INVESTIGATED THE UNDERLYING MECHANISMS. VARIOUS MODELS OF LIVER FIBROSIS INCLUDING MDR2(-/-), BILE DUCT LIGATION (BDL) AND CCL(4) MICE WERE ADAPTED. WE FOUND THAT EZH2 WAS MARKEDLY UPREGULATED AND CORRELATED WITH H19 AND FIBROTIC MARKERS EXPRESSION IN THESE MODELS. ADMINISTRATION OF EZH2 INHIBITOR 3-DZNEP CAUSED SIGNIFICANT PROTECTIVE EFFECTS IN THESE MODELS. FURTHERMORE, TREATMENT WITH 3-DZNEP OR GSK126 SIGNIFICANTLY INHIBITED PRIMARY HSC ACTIVATION AND PROLIFERATION IN TGF-BETA-TREATED HSCS AND H19-OVEREXPREESING LX2 CELLS IN VIVO. USING RNA-PULL DOWN ASSAY COMBINED WITH RNA IMMUNOPRECIPITATION, WE DEMONSTRATED THAT H19 COULD DIRECTLY BIND TO EZH2. INTEGRATED ANALYSIS OF RNA-SEQUENCING (RNA-SEQ) AND CHROMATIN IMMUNOPRECIPITATION SEQUENCING (CHIP-SEQ) FURTHER REVEALED THAT H19 REGULATED THE REPROGRAMMING OF EZH2-MEDIATED H3K27ME3 PROFILES, WHICH EPIGENETICALLY PROMOTED SEVERAL PATHWAYS FAVORING HSCS ACTIVATION AND PROLIFERATION, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION AND WNT/BETA-CATENIN SIGNALING. IN CONCLUSION, HIGHLY EXPRESSED H19 IN CHRONIC LIVER DISEASES PROMOTES FIBROGENESIS BY REPROGRAMMING EZH2-MEDIATED EPIGENETIC REGULATION OF HSCS ACTIVATION. TARGETING THE H19-EZH2 INTERACTION MAY SERVE AS A NOVEL THERAPEUTIC APPROACH FOR LIVER FIBROSIS. 2023