1 1032 123 CISPLATIN NEPHROTOXICITY: NEW INSIGHTS AND THERAPEUTIC IMPLICATIONS. CISPLATIN IS AN EFFECTIVE CHEMOTHERAPEUTIC AGENT FOR VARIOUS SOLID TUMOURS, BUT ITS USE IS LIMITED BY ADVERSE EFFECTS IN NORMAL TISSUES. IN PARTICULAR, CISPLATIN IS NEPHROTOXIC AND CAN CAUSE ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE. PRECLINICAL STUDIES HAVE PROVIDED INSIGHTS INTO THE CELLULAR AND MOLECULAR MECHANISMS OF CISPLATIN NEPHROTOXICITY, WHICH INVOLVE INTRACELLULAR STRESSES INCLUDING DNA DAMAGE, MITOCHONDRIAL PATHOLOGY, OXIDATIVE STRESS AND ENDOPLASMIC RETICULUM STRESS. STRESS RESPONSES, INCLUDING AUTOPHAGY, CELL-CYCLE ARREST, SENESCENCE, APOPTOSIS, PROGRAMMED NECROSIS AND INFLAMMATION HAVE KEY ROLES IN THE PATHOGENESIS OF CISPLATIN NEPHROTOXICITY. IN ADDITION, EMERGING EVIDENCE SUGGESTS A CONTRIBUTION OF EPIGENETIC CHANGES TO CISPLATIN-INDUCED ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE. FURTHER RESEARCH IS NEEDED TO DETERMINE HOW THESE PATHWAYS ARE INTEGRATED AND TO IDENTIFY THE CELL TYPE-SPECIFIC ROLES OF CRITICAL MOLECULES INVOLVED IN REGULATED NECROSIS, INFLAMMATION AND EPIGENETIC MODIFICATIONS IN CISPLATIN NEPHROTOXICITY. A NUMBER OF POTENTIAL THERAPEUTIC TARGETS FOR CISPLATIN NEPHROTOXICITY HAVE BEEN IDENTIFIED. HOWEVER, THE EFFECTS OF RENOPROTECTIVE STRATEGIES ON THE EFFICACY OF CISPLATIN CHEMOTHERAPY NEEDS TO BE THOROUGHLY EVALUATED. FURTHER RESEARCH USING TUMOUR-BEARING ANIMALS, MULTI-OMICS AND GENOME-WIDE ASSOCIATION STUDIES WILL ENABLE A COMPREHENSIVE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR MECHANISMS OF CISPLATIN NEPHROTOXICITY AND POTENTIALLY LEAD TO THE IDENTIFICATION OF SPECIFIC TARGETS TO PROTECT THE KIDNEY WITHOUT COMPROMISING THE CHEMOTHERAPEUTIC EFFICACY OF CISPLATIN. 2023 2 2285 30 EPIGENETIC REGULATION IN KIDNEY TOXICITY: INSIGHTS FROM CISPLATIN NEPHROTOXICITY. NEPHROTOXICITY, AS A RESULT OF THE EXPOSURE OF KIDNEY TO ENDOGENOUS AND EXOGENOUS TOXINS, IS AN IMPORTANT FACTOR FOR ACUTE KIDNEY INJURY AND THE DEVELOPMENT OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CISPLATIN IS AMONG THE MOST WIDELY STUDIED KIDNEY TOXICANTS. IN THE PAST DECADE, EPIGENETIC REGULATION HAS EMERGED AS A NOTABLE PATHOGENIC MECHANISM IN CISPLATIN NEPHROTOXICITY, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS. IN THIS REVIEW, WE USE CISPLATIN NEPHROTOXICITY AS AN EXAMPLE TO HIGHLIGHT THE EPIGENETIC ALTERATION, FUNCTION, AND UNDERLYING MECHANISM IN KIDNEY TOXICITY. THE STUDY OF EPIGENETIC REGULATION IN KIDNEY TOXICITY IS STILL IN ITS INFANCY, AND FURTHER INVESTIGATION WILL BRING NEW INSIGHTS FOR THE DEVELOPMENT OF NOVEL DIAGNOSTIC BIOMARKERS AND THERAPEUTIC INTERVENTIONS. 2019 3 3876 28 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 3623 34 IN VIVO COMET ASSAY ON ISOLATED KIDNEY CELLS TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS OR CYTOTOXIC COMPOUNDS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE THE ABILITY OF THE ALKALINE IN VIVO COMET ASSAY (PH>13) TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS WHEN PERFORMED ON FRESHLY ISOLATED KIDNEY CELLS AND TO DETERMINE THE POSSIBLE INTERFERENCE OF CYTOTOXICITY BY ASSESSING DNA DAMAGE INDUCED BY RENAL GENOTOXIC, EPIGENETIC OR TOXIC COMPOUNDS AFTER ENZYMATIC ISOLATION OF KIDNEY CELLS FROM OFA SPRAGUE-DAWLEY MALE RATS. THE ABILITY OF THE COMET ASSAY TO DISTINGUISH (1) GENOTOXICITY VERSUS CYTOTOXICITY AND (2) GENOTOXIC VERSUS NON-GENOTOXIC (EPIGENETIC) CARCINOGENS, WAS THUS INVESTIGATED BY STUDYING FIVE KNOWN GENOTOXIC RENAL CARCINOGENS ACTING THROUGH DIVERSE MECHANISMS OF ACTION, I.E. STREPTOZOTOCIN, ARISTOLOCHIC ACIDS, 2-NITROANISOLE, POTASSIUM BROMATE AND CISPLATIN, TWO RODENT RENAL EPIGENETIC CARCINOGENS: D-LIMONENE AND CICLOSPORINE AND TWO NEPHROTOXIC COMPOUNDS: STREPTOMYCIN AND INDOMETHACIN. ANIMALS WERE TREATED ONCE WITH THE TEST COMPOUND BY THE APPROPRIATE ROUTE OF ADMINISTRATION AND GENOTOXIC EFFECTS WERE MEASURED AT THE TWO SAMPLING TIMES OF 3-6 AND 22-26H AFTER TREATMENT. REGARDING THE TISSUE PROCESSING, THE LIMITED BACKGROUND LEVEL OF DNA MIGRATION OBSERVED IN THE NEGATIVE CONTROL GROUPS THROUGHOUT ALL EXPERIMENTS DEMONSTRATED THAT THE ENZYMATIC ISOLATION METHOD IMPLEMENTED IN THE CURRENT STUDY IS APPROPRIATE. ON THE OTHER HAND, STREPTOZOTOCIN, 20MG/KG, USED AS POSITIVE REFERENCE CONTROL CONCURRENTLY TO EACH ASSAY, CAUSED A CLEAR INCREASE IN THE MEAN OLIVE TAIL MOMENT MEDIAN VALUE, WHICH ALLOWS VALIDATING THE CURRENT METHODOLOGY. UNDER THESE EXPERIMENTAL CONDITIONS, THE IN VIVO RODENT COMET ASSAY DEMONSTRATED GOOD SENSITIVITY AND GOOD SPECIFICITY: ALL THE FIVE RENAL GENOTOXIC CARCINOGENS WERE CLEARLY DETECTED IN AT LEAST ONE EXPRESSION PERIOD EITHER DIRECTLY OR INDIRECTLY, AS IN THE CASE OF CISPLATIN: FOR THIS CROSS-LINKING AGENT, THE SIGNIFICANT DECREASE IN DNA MIGRATION OBSERVED UNDER STANDARD ELECTROPHORESIS CONDITIONS WAS CLEARLY AMPLIFIED WHEN THE DURATION OF ELECTROPHORESIS WAS INCREASED UP TO 40MIN. IN CONTRAST, EPIGENETIC AND NEPHROTOXIC COMPOUNDS FAILED TO INDUCE ANY SIGNIFCANT INCREASE IN DNA MIGRATION. IN CONCLUSION, THE IN VIVO RODENT COMET ASSAY PERFORMED ON ISOLATED KIDNEY CELLS COULD BE USED AS A TOOL TO INVESTIGATE THE GENOTOXIC POTENTIAL OF A TEST COMPOUND IF NEOPLASIC/PRENEOPLASIC CHANGES OCCUR AFTER SUBCHRONIC OR CHRONIC TREATMENTS, IN ORDER TO DETERMINE THE ROLE OF GENOTOXICITY IN TUMOR INDUCTION. MOREOVER, THE EPIGENETIC CARCINOGENS AND CYTOTOXIC COMPOUNDS DISPLAYED CLEARLY NEGATIVE RESPONSES IN THIS STUDY. THESE RESULTS ALLOW EXCLUDING A DNA DIRECT-ACTING MECHANISM OF ACTION AND CAN THUS SUGGEST THAT A THRESHOLD EXISTS. THEREFORE, THE CURRENT IN VIVO RODENT COMET ASSAY COULD CONTRIBUTE TO ELUCIDATE AN EPIGENETIC MECHANISM AND THUS, TO UNDERTAKE A RISK ASSESSMENT ASSOCIATED WITH HUMAN USE, DEPENDING ON THE EXPOSURE LEVEL. 2007 5 4742 31 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN. 2022 6 5337 23 QUANTITATIVE ANALYSIS OF HISTONE H3 AND H4 POST-TRANSLATIONAL MODIFICATIONS IN DOXORUBICIN-RESISTANT LEUKEMIA CELLS. THE EPIGENETIC REMODELING OF CHROMATIN THROUGH HISTONE MODIFICATIONS HAS BEEN WIDELY IMPLICATED IN DRUG RESISTANCE OF CANCER CELLS. HOWEVER, WHETHER EPIGENETIC MECHANISMS CONTRIBUTE SPECIFICALLY TO DOXORUBICIN RESISTANCE IN LEUKEMIA HAS NOT BEEN CAREFULLY EXAMINED. USING A STABLE AND SENSITIVE WORKFLOW BASED ON LC-MS, WE QUANTITATIVELY COMPARED THE EXTENTS OF METHYLATION AND ACETYLATION OF HISTONE H3 AND H4 IN ACUTE LEUKEMIA CELL LINE HL60 AND ITS DOXORUBICIN-RESISTANT DERIVATIVE, HL60/ADR, AS WELL AS THE CHRONIC LEUKEMIA CELL LINE K562 AND ITS DOXORUBICIN-RESISTANT DERIVATIVE, K562/ADR. WE FOUND THAT INCREASED LEVELS OF H3K9 METHYLATION, H3K14, H3K18 AND H3K23 ACETYLATION, AND POTENTIALLY H4K20 METHYLATION, ARE ASSOCIATED WITH DRUG RESISTANCE IN BOTH CELLS. OUR RESULTS DEMONSTRATED THAT THE DOXORUBICIN-RESISTANT ACUTE AND CHRONIC LEUKEMIA CELL LINES MAY SHARE A COMMON EPIGENETIC MECHANISM THAT INVOLVES A COMBINATION OF TRANSCRIPTIONAL ACTIVATION AND SILENCING. 2016 7 6421 31 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 8 979 34 CHRONIC OXIDATIVE STRESS INCREASES RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY IN RENAL CARCINOMA CELLS POTENTIALLY THROUGH EPIGENETIC MECHANISM. RENAL CELL CARCINOMA IS THE MOST COMMON FORM OF KIDNEY CANCER AND IS HIGHLY RESISTANT TO CHEMOTHERAPY. ALTHOUGH THE ROLE OF OXIDATIVE STRESS IN KIDNEY CANCER IS KNOWN, THE CHEMOTHERAPEUTIC RESPONSE OF CANCER CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS IS NOT CLEAR. HENCE, THE EFFECT OF OXIDATIVE STRESS ON SENSITIVITY TO DOXORUBICIN-INDUCED CYTOTOXICITY WAS EVALUATED USING AN IN VITRO MODEL OF HUMAN KIDNEY CANCER CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. RESULTS OF MTT- AND ANCHORAGE-INDEPENDENT GROWTH ASSAYS AND CELL CYCLE ANALYSIS REVEALED SIGNIFICANT DECREASE IN SENSITIVITY TO DOXORUBICIN IN CAKI-1 CELLS ADAPTED TO OXIDATIVE STRESS. CHANGES IN THE EXPRESSION OF GENES INVOLVED IN DRUG TRANSPORT, CELL SURVIVAL, AND DNA REPAIR-DEPENDENT APOPTOSIS FURTHER CONFIRMED INCREASED RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY IN THESE CELLS. DECREASED EXPRESSION OF MISMATCH REPAIR (MMR) GENE MSH2 IN CELLS EXPOSED TO OXIDATIVE STRESS SUGGESTS THAT LOSS OF MMR-DEPENDENT APOPTOSIS COULD BE A POTENTIAL MECHANISM FOR INCREASED RESISTANCE TO DOXORUBICIN-INDUCED CYTOTOXICITY. ADDITIONALLY, DOWNREGULATION OF HDAC1, AN INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION, AND HYPERMETHYLATION OF MSH2 PROMOTER WERE ALSO OBSERVED IN CAKI-1 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. DNA-DEMETHYLATING AGENT 5-AZA-2DC SIGNIFICANTLY RESTORED THE EXPRESSION OF MSH2 AND DOXORUBICIN-INDUCED CYTOTOXICITY IN CAKI-1 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS, SUGGESTING THE ROLE OF DNA HYPERMETHYLATION IN INACTIVATION OF MSH2 EXPRESSION AND CONSEQUENTLY MMR-DEPENDENT APOPTOSIS IN THESE CELLS. IN SUMMARY, THIS STUDY FOR THE FIRST TIME PROVIDES DIRECT EVIDENCE FOR THE ROLE OF OXIDATIVE STRESS IN CHEMOTHERAPEUTIC RESISTANCE IN RENAL CARCINOMA CELLS POTENTIALLY THROUGH EPIGENETIC MECHANISM. 2016 9 5994 33 TGFBETA-INCURRED EPIGENETIC ABERRATIONS OF MIRNA AND DNA METHYLTRANSFERASE SUPPRESS KLOTHO AND POTENTIATE RENAL FIBROSIS. RENAL FIBROSIS IS A COMMON PATHOLOGICAL FEATURE OF CHRONIC KIDNEY DISEASES (CKD) AND ITS DEVELOPMENT AND PROGRESSION ARE SIGNIFICANTLY AFFECTED BY EPIGENETIC MODIFICATIONS SUCH AS ABERRANT MIRNA AND DNA METHYLATION. KLOTHO IS AN ANTI-AGING AND ANTI-FIBROTIC PROTEIN AND ITS EARLY DECLINE AFTER RENAL INJURY IS REPORTEDLY ASSOCIATED WITH ABERRANT DNA METHYLATION. HOWEVER, THE KEY UPSTREAM PATHOLOGICAL MEDIATORS AND THE MOLECULAR CASCADE LEADING TO EPIGENETIC KLOTHO SUPPRESSION ARE NOT EXCLUSIVELY ESTABLISHED. HERE WE INVESTIGATE THE EPIGENETIC MECHANISM OF KLOTHO DEFICIENCY AND ITS FUNCTIONAL RELEVANCE IN RENAL FIBROGENESIS. FIBROTIC KIDNEYS INDUCED BY UNILATERAL URETERAL OCCLUSION (UUO) DISPLAYED MARKED KLOTHO SUPPRESSION AND THE PROMOTER HYPERMETHYLATION. THESE ABNORMALITIES WERE LIKELY DUE TO DEREGULATED TRANSFORMING GROWTH FACTOR-BETA (TGFBETA) SINCE TGFBETA ALONE CAUSED THE SIMILAR EPIGENETIC ABERRATIONS IN CULTURED RENAL CELLS AND TGFBETA BLOCKADE PREVENTED THE ALTERATIONS IN UUO KIDNEY. FURTHER INVESTIGATION REVEALED THAT TGFBETA ENHANCED DNA METHYLTRANSFERASE (DNMT) 1 AND DNMT3A VIA INHIBITING MIR-152 AND MIR-30A IN BOTH RENAL CELLS AND FIBROTIC KIDNEYS. ACCORDINGLY THE BLOCKADE OF EITHER TGFBETA SIGNALING OR DNMT1/3A ACTIVITIES SIGNIFICANTLY RECOVERED THE KLOTHO LOSS AND ATTENUATED PRO-FIBROTIC PROTEIN EXPRESSION AND RENAL FIBROSIS. MOREOVER, KLOTHO KNOCKDOWN BY RNA INTERFERENCES ABOLISHED THE ANTI-FIBROTIC EFFECTS OF DNMT INHIBITION IN BOTH TGFBETA-TREATED RENAL CELL AND UUO KIDNEY, INDICATING THAT TGFBETA-MEDIATED MIR-152/30A INHIBITIONS, DNMT1/3A ABERRATIONS AND SUBSEQUENT KLOTHO LOSS CONSTITUTE A CRITICAL REGULATORY LOOP THAT ELIMINATES KLOTHO'S ANTI-FIBROTIC ACTIVITIES AND POTENTIATES RENAL FIBROGENESIS. THUS, OUR STUDY ELABORATES A NOVEL EPIGENETIC CASCADE OF RENAL FIBROGENESIS AND REVEALS THE POTENTIAL THERAPEUTIC TARGETS FOR TREATING THE RENAL FIBROSIS-ASSOCIATED KIDNEY DISEASES. 2017 10 3367 28 HISTONE METHYLTRANSFERASE EZH2: A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A HISTONE-LYSINE N-METHYLTRANSFERASE ENZYME THAT CATALYZES THE ADDITION OF METHYL GROUPS TO HISTONE H3 AT LYSINE 27, LEADING TO GENE SILENCING. MUTATION OR OVER-EXPRESSION OF EZH2 HAS BEEN LINKED TO MANY CANCERS INCLUDING RENAL CARCINOMA. RECENT STUDIES HAVE SHOWN THAT EZH2 EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY (AKI), RENAL FIBROSIS, DIABETIC NEPHROPATHY, LUPUS NEPHRITIS (LN), AND RENAL TRANSPLANTATION REJECTION. THE PHARMACOLOGICAL AND/OR GENETIC INHIBITION OF EZH2 CAN ALLEVIATE AKI, RENAL FIBROSIS, AND LN, BUT POTENTIATE PODOCYTE INJURY IN ANIMAL MODELS, SUGGESTING THAT THE FUNCTIONAL ROLE OF EZH2 VARIES WITH RENAL CELL TYPE AND DISEASE MODEL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE OF EZH2 IN THE PATHOLOGY OF RENAL INJURY AND RELEVANT MECHANISMS AND HIGHLIGHT EZH2 AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2021 11 4121 39 MECHANISMS OF CHEMICALLY INDUCED RENAL CARCINOGENESIS IN THE LABORATORY RODENT. LABORATORY STUDIES WITH CLASSICAL RENAL CARCINOGENS IN THE RAT AND MOUSE, AS WELL AS RESEARCH INVESTIGATION WITH SOME OF THE CHEMICALS PROVING POSITIVE FOR THE KIDNEY IN NATIONAL TOXICOLOGY PROGRAM CARCINOGENICITY BIOASSAYS, HAVE DEMONSTRATED THE EXISTENCE OF A RANGE OF DIVERSE MECHANISMS UNDERLYING RODENT KIDNEY CARCINOGENESIS. THE CLASSICAL CARCINOGENS USED AS EXPERIMENTAL MODELS FOR STUDYING RENAL TUMOR PATHOGENESIS, SUCH AS THE NITROSAMINES, ARE GENOTOXIC AND INTERACT DIRECTLY WITH DNA, FORMING DNA ADDUCTS WITH MUTAGENIC POTENTIAL. IN CONTRAST, POTASSIUM BROMATE AND FERRIC NITRILOTRIACETATE (FE-NTA), ALSO EFFECTIVE RENAL CARCINOGENS, APPEAR TO CAUSE INDIRECT DAMAGE TO DNA MEDIATED BY OXIDATIVE STRESS. A NUMBER OF NONGENOTOXIC CHEMICALS ARE ASSOCIATED WITH EPIGENETIC RENAL TUMOR INDUCTION IN RODENTS, AND THE ACTIVITY OF THESE TENDS TO INVOLVE PROLONGED STIMULATION OF CELL PROLIFERATION THROUGHOUT THE DURATION OF EXPOSURE. THIS MODE OF ACTION REFLECTS A SUSTAINED REGENERATIVE RESPONSE, EITHER DUE TO DIRECT CHEMICAL TOXICITY TO THE TUBULE CELLS, AS WITH CHLOROFORM, OR TO INDIRECT CYTOTOXICITY ASSOCIATED WITH LYSOSOMAL OVERLOAD, AS IN ALPHA2U-GLOBULIN ACCUMULATION IN MALE RATS RESULTING FROM THE ADMINISTRATION OF SUCH CHEMICALS AS D-LIMONENE AND TETRACHLOROETHYLENE. THE HISTOPATHOLOGIC NATURE OF HYDROQUINONE RENAL CARCINOGENESIS SUGGESTS THAT AN ADDITIONAL EPIGENETIC PATHWAY TO RENAL TUBULE TUMOR FORMATION IN RATS MAY BE THROUGH CHEMICAL-MEDIATED EXACERBATION OF, AND INTERACTION WITH, THE AGE-RELATED SPONTANEOUS RENAL DISEASE, CHRONIC PROGRESSIVE NEPHROPATHY. THESE VARIOUS MECHANISTIC PATHWAYS HAVE IMPLICATIONS FOR THE NATURE OF THE INDUCED CANCER PROCESS WITH RESPECT TO TUMOR INCIDENCE, LATENCY, MALIGNANCY, AND SEX PREDISPOSITION. 1998 12 3048 28 GENOME-WIDE ANALYSIS REVEALED THAT DZNEP REDUCES TUBULOINTERSTITIAL FIBROSIS VIA DOWN-REGULATION OF PRO-FIBROTIC GENES. TUBULOINTERSTITIAL FIBROSIS HAS BEEN RECENTLY REPORTED TO BE CAUSED BY THE COLLAPSE OF THE EPIGENETIC REGULATION OF KIDNEY DISEASES. WE EXAMINED WHETHER PHARMACOLOGICAL INHIBITION OF HISTONE MODIFICATION IS EFFECTIVE AGAINST RENAL FIBROSIS. DZNEP (3-DEAZANEPLANOCIN A) WAS ORIGINALLY DEVELOPED AS AN ANTI-CANCER DRUG TO INHIBIT THE REPRESSIVE HISTONE MARK, H3K27ME3. WE USED A MODEL OF CHRONIC TUBULOINTERSTITIAL FIBROSIS INDUCED BY UNILATERAL ISCHAEMIA/REPERFUSION AND ADMINISTERED DZNEP INTRAVENOUSLY TO THE MICE FOR 8 WEEKS. WE FOUND DZNEP CONTRIBUTES TO THE REDUCTION OF TUBULOINTERSTITIAL FIBROSIS. WE SELECTED ONLY TUBULAR CELLS FROM IN VIVO SAMPLES USING LASER-CAPTURE MICRODISSECTION BECAUSE EPIGENETIC REGULATION IS SPECIFIC TO THE CELL TYPES, AND WE FOCUSED ON THE CHANGES IN THE TUBULAR CELLS. WE PERFORMED A GENOME-WIDE ANALYSIS OF TUBULAR CELLS USING HIGH-THROUGHPUT SEQUENCING (RNA-SEQ) TO IDENTIFY NOVEL EPIGENETIC FACTORS ASSOCIATED WITH RENAL FIBROSIS. WE FOUND THAT PRO-FIBROTIC GENES SUCH AS COL3A1 (COLLAGEN TYPE 3A1) AND TIMP2 (TISSUE INHIBITOR OF METALLOPROTEINASE 2) WERE SUPPRESSED BY DZNEP IN VIVO. IN ADDITION, PRO-FIBROTIC GENES SUCH AS COL4A1 (COLLAGEN TYPE 4A1), TIMP2 AND MMP14 WERE DOWN-REGULATED BY DZNEP IN VITRO. IN CONCLUSION, WE FOUND THAT PHARMACOLOGICAL EPIGENETIC MODIFICATION BY DZNEP DECREASED THE EXPRESSION LEVELS OF FIBROGENIC GENES IN TUBULAR CELLS AND INHIBITED TUBULOINTERSTITIAL FIBROSIS. 2018 13 439 30 ANTILEUKEMIC ACTIVITY OF VALPROIC ACID IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS DEFINED BY MICROARRAY ANALYSIS. EPIGENETIC CODE MODIFICATIONS BY HISTONE DEACETYLASE INHIBITORS HAVE RECENTLY BEEN PROPOSED AS POTENTIAL NEW THERAPIES FOR HEMATOLOGICAL MALIGNANCIES. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REMAINS INCURABLE DESPITE THE INTRODUCTION OF NEW TREATMENTS. CLL B CELLS ARE CHARACTERIZED BY AN APOPTOSIS DEFECT RATHER THAN EXCESSIVE PROLIFERATION, BUT PROLIFERATION CENTERS HAVE BEEN FOUND IN ORGANS SUCH AS THE BONE MARROW AND LYMPH NODES. IN THIS STUDY, WE ANALYZED GENE EXPRESSION MODIFICATIONS IN CLL B CELLS AFTER TREATMENT WITH VALPROIC ACID (VPA), A WELL-TOLERATED ANTI-EPILEPTIC DRUG WITH HDAC INHIBITORY ACTIVITY. CLL B CELLS OBTAINED FROM 14 PATIENTS WERE TREATED IN VITRO WITH A CONCENTRATION OF 1 MM VPA FOR 4 H. VPA EFFECTS ON GENE EXPRESSION WERE THEREAFTER STUDIED USING AFFYMETRIX TECHNOLOGY, AND SOME IDENTIFIED GENES WERE VALIDATED BY REAL-TIME PCR AND WESTERN BLOT. WE OBSERVED THAT VPA INDUCED APOPTOSIS BY DOWNREGULATING SEVERAL ANTI-APOPTOTIC GENES AND BY UPREGULATING PRO-APOPTOTIC GENES. FURTHERMORE, VPA SIGNIFICANTLY INCREASED CHEMOSENSITIVITY TO FLUDARABINE, FLAVOPIRIDOL, BORTEZOMIB, THALIDOMIDE AND LENALIDOMIDE. VPA INHIBITED THE PROLIFERATION OF CPG/IL2-STIMULATED CLL B CELLS AND MODULATED MANY CELL CYCLE MESSENGER RNAS. IN CONCLUSION, EXPOSURE OF CLL B CELLS TO VPA INDUCED APOPTOSIS, POTENTIATED CHEMOTHERAPEUTIC AGENT EFFECTS AND INHIBITED PROLIFERATION. THESE DATA STRONGLY SUGGEST THE USE OF VPA IN CLL TREATMENT, PARTICULARLY IN COMBINATION WITH ANTILEUKEMIA AGENTS. 2009 14 1906 27 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS. 2018 15 98 26 A PROOF-OF-CONCEPT FOR EPIGENETIC THERAPY OF TISSUE FIBROSIS: INHIBITION OF LIVER FIBROSIS PROGRESSION BY 3-DEAZANEPLANOCIN A. THE PROGRESSION OF FIBROSIS IN CHRONIC LIVER DISEASE IS DEPENDENT UPON HEPATIC STELLATE CELLS (HSCS) TRANSDIFFERENTIATING TO A MYOFIBROBLAST-LIKE PHENOTYPE. THIS PIVOTAL PROCESS IS CONTROLLED BY ENZYMES THAT REGULATE HISTONE METHYLATION AND CHROMATIN STRUCTURE, WHICH MAY BE TARGETS FOR DEVELOPING ANTI-FIBROTICS. THERE IS LIMITED PRE-CLINICAL EXPERIMENTAL SUPPORT FOR THE POTENTIAL TO THERAPEUTICALLY MANIPULATE EPIGENETIC REGULATORS IN FIBROSIS. IN ORDER TO LEARN IF EPIGENETIC TREATMENT CAN HALT THE PROGRESSION OF PRE-ESTABLISHED LIVER FIBROSIS, WE TREATED MICE WITH THE HISTONE METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A (DZNEP) IN A NAKED FORM OR BY SELECTIVELY TARGETING HSC-DERIVED MYOFIBROBLASTS VIA AN ANTIBODY-LIPOSOME-DZNEP TARGETING VEHICLE. WE DISCOVERED THAT DZNEP TREATMENT INHIBITED MULTIPLE HISTONE METHYLATION MODIFICATIONS, INDICATIVE OF A BROADER SPECIFICITY THAN PREVIOUSLY REPORTED. THIS BROAD EPIGENETIC REPRESSION WAS ASSOCIATED WITH THE SUPPRESSION OF FIBROSIS PROGRESSION AS ASSESSED BOTH HISTOLOGICALLY AND BIOCHEMICALLY. THE ANTI-FIBROTIC EFFECT OF DZNEP WAS REPRODUCED WHEN THE DRUG WAS SELECTIVELY TARGETED TO HSC-DERIVED MYOFIBROBLASTS. THEREFORE, THE IN VIVO MODULATION OF HSC HISTONE METHYLATION IS SUFFICIENT TO HALT PROGRESSION OF FIBROSIS IN THE CONTEXT OF CONTINUOUS LIVER DAMAGE. THIS DISCOVERY AND OUR NOVEL HSC-TARGETING VEHICLE, WHICH AVOIDS THE UNWANTED EFFECTS OF EPIGENETIC DRUGS ON PARENCHYMAL LIVER CELLS, REPRESENTS AN IMPORTANT PROOF-OF-CONCEPT FOR EPIGENETIC TREATMENT OF LIVER FIBROSIS. 2017 16 1762 34 EARLY TRANSCRIPTIONAL ALTERATION OF HISTONE DEACETYLASES IN A MURINE MODEL OF DOXORUBICIN-INDUCED CARDIOMYOPATHY. DOXORUBICIN IS A POTENT CHEMOTHERAPEUTIC AGENT THAT IS WIDELY-USED TO TREAT A VARIETY OF CANCERS BUT CAUSES ACUTE AND CHRONIC CARDIAC INJURY, SEVERELY LIMITING ITS USE. CLINICALLY, THE ACUTE SIDE EFFECTS OF DOXORUBICIN ARE MOSTLY MANAGEABLE, WHEREAS THE DELAYED CONSEQUENCES CAN LEAD TO LIFE-THREATENING HEART FAILURE, EVEN DECADES AFTER CANCER TREATMENT. THE CARDIOTOXICITY OF DOXORUBICIN IS SUBJECT TO A CRITICAL CUMULATIVE DOSE AND SO DOSAGE LIMITATION IS CONSIDERED TO BE THE BEST WAY TO REDUCE THESE EFFECTS. HENCE, A NUMBER OF STUDIES HAVE DEFINED A "SAFE DOSE" OF THE DRUG, BOTH IN ANIMAL MODELS AND CLINICAL SETTINGS, WITH THE AIM OF AVOIDING LONG-TERM CARDIAC EFFECTS. HERE WE SHOW THAT A DOSE GENERALLY CONSIDERED AS SAFE IN A MOUSE MODEL CAN INDUCE HARMFUL CHANGES IN THE MYOCARDIUM, AS EARLY AS 2 WEEKS AFTER INFUSION. THE ADVERSE CHANGES INCLUDE THE DEVELOPMENT OF FIBROTIC LESIONS, DISARRAY OF CARDIOMYOCYTES AND A MAJOR TRANSCRIPTION DYSREGULATION. IMPORTANTLY, LOW-DOSE DOXORUBICIN CAUSED SPECIFIC CHANGES IN THE TRANSCRIPTIONAL PROFILE OF SEVERAL HISTONE DEACETYLASES (HDACS) WHICH ARE EPIGENETIC REGULATORS OF CARDIAC REMODELLING. THIS SUGGESTS THAT CARDIOPROTECTIVE THERAPIES, AIMED AT MODULATING HDACS DURING DOXORUBICIN TREATMENT, DESERVE FURTHER EXPLORATION. 2017 17 6882 19 [RESEARCH PROGRESS ON NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. PRIMARY LIVER CANCER ARISES FROM CHRONIC LIVER DISEASE, AND CIRRHOTIC LIVER GRADUALLY DEVELOPS INTO DYSPLASTIC NODULES THAT EVENTUALLY FORM MALIGNANT TUMORS. IN RECENT YEARS, MOLECULAR BIOTECHNOLOGY DEVELOPMENT HAS DEEPENED PEOPLE'S UNDERSTANDING ON THE PATHOGENESIS OF LIVER CANCER. EPIGENETIC MODIFICATIONS PLAY A SIGNIFICANT ROLE IN DNA METHYLATION, NON-CODING RNAS, CHROMATIN REMODELING, AND HISTONE MODIFICATION. THIS REVIEW FOCUSES ON THE PROGRESS OF CURRENTLY IMPLICATED NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA, AND ITS POTENTIAL APPLICATION IN IMPROVING THE DIAGNOSIS AND TREATMENT. 2018 18 4704 26 NITRATION OF DISTINCT TYROSINE RESIDUES CAUSES INACTIVATION OF HISTONE DEACETYLASE 2. HISTONE DEACETYLASES (HDACS) ARE KEY MOLECULES INVOLVED IN EPIGENETIC REGULATION OF GENE EXPRESSION. WE HAVE PREVIOUSLY DEMONSTRATED THAT OXIDATIVE STRESS CAUSED A REDUCTION IN HDAC2, RESULTING IN AMPLIFIED INFLAMMATION AND REDUCED CORTICOSTEROID RESPONSIVENESS. HERE WE SHOWED NITRATIVE/OXIDATIVE STRESS REDUCED HDAC2 EXPRESSION VIA NITRATION OF DISTINCT TYROSINE RESIDUES. PEROXYNITRITE, HYDROGEN PEROXIDE AND CIGARETTE SMOKE-CONDITIONED MEDIUM REDUCED HDAC2 EXPRESSION IN A549 EPITHELIAL CELLS IN VITRO. THIS REDUCTION WAS DUE TO INCREASED PROTEASOMAL DEGRADATION FOLLOWING UBIQUITINATION RATHER THAN REDUCTION OF MRNA EXPRESSION OR STABILITY. HDAC2 WAS NITRATED UNDER NITRATIVE/OXIDATIVE STRESS AND IN THE PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTAGENESIS STUDIES REPLACING TYROSINE (Y) RESIDUES WITH ALANINE REVEALED THAT Y253 IS AT LEAST PARTLY RESPONSIBLE FOR THE PROTEASOMAL DEGRADATION OF HDAC2 UNDER NITRATIVE STRESS. THUS, NITRATION OF DISTINCT TYROSINE RESIDUES MODIFIES BOTH THE EXPRESSION AND ACTIVITY OF HDAC2, HAVING AN IMPACT ON EPIGENETIC REGULATION. 2009 19 6321 20 THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN KIDNEY DISEASES. METHYLATION CAN OCCUR IN BOTH HISTONES AND NON-HISTONES. KEY LYSINE AND ARGININE METHYLTRANSFERASES UNDER INVESTIGATION FOR RENAL DISEASE TREATMENT INCLUDE ENHANCER OF ZESTE HOMOLOG 2 (EZH2), G9A, DISRUPTOR OF TELOMERIC SILENCING 1-LIKE PROTEIN (DOT1L), AND PROTEIN ARGININE METHYLTRANSFERASES (PRMT) 1 AND 5. RECENT STUDIES HAVE SHOWN THAT METHYLTRANSFERASES EXPRESSION AND ACTIVITY ARE ALSO INCREASED IN SEVERAL ANIMAL MODELS OF KIDNEY INJURY, SUCH AS ACUTE KIDNEY INJURY(AKI), OBSTRUCTIVE NEPHROPATHY, DIABETIC NEPHROPATHY AND LUPUS NEPHRITIS. THE INHIBITION OF MOST METHYLTRANSFERASES CAN ATTENUATE KIDNEY INJURY, WHILE THE ROLE OF METHYLTRANSFERASE IN DIFFERENT ANIMAL MODELS REMAINS CONTROVERSIAL. IN THIS ARTICLE, WE SUMMARIZE THE ROLE AND MECHANISM OF LYSINE METHYLTRANSFERASE AND ARGININE METHYLTRANSFERASE IN VARIOUS KIDNEY DISEASES AND HIGHLIGHT METHYLTRANSFERASE AS A POTENTIAL THERAPEUTIC TARGET FOR KIDNEY DISEASES. 2022 20 171 36 ABROGATION OF HISTONE DEACETYLASES (HDACS) DECREASES SURVIVAL OF CHRONIC MYELOID LEUKEMIA CELLS: NEW INSIGHT INTO ATTENUATING EFFECTS OF THE PI3K/C-MYC AXIS ON PANOBINOSTAT CYTOTOXICITY. ALTHOUGH THE IDENTIFICATION OF TYROSINE KINASE INHIBITORS (TKIS) HAS CHANGED THE TREATMENT PARADIGM OF MANY CANCER TYPES INCLUDING CHRONIC MYELOID LEUKEMIA (CML), STILL ADJUSTMENT OF NEOPLASTIC CELLS TO CYTOTOXIC EFFECTS OF ANTICANCER DRUGS IS A SERIOUS CHALLENGE. IN THE AREA OF DRUG RESISTANCE, EPIGENETIC ALTERATIONS ARE AT THE CENTER OF ATTENTION AND THE PRESENT STUDY AIMED TO EVALUATE WHETHER BLOCKAGE OF EPIGENETICS MECHANISMS USING A PAN-HISTONE DEACETYLASE (HDAC) INHIBITOR INDUCES CELL DEATH IN CML-DERIVED K562 CELLS. WE FOUND THAT THE ABROGATION OF HDACS USING PANOBINOSTAT RESULTED IN A REDUCTION IN SURVIVAL OF THE K562 CELL LINE THROUGH P27-MEDIATED CELL CYCLE ARREST. NOTEWORTHY, THE RESULTS OF THE SYNERGISTIC EXPERIMENTS REVEALED THAT HDAC SUPPRESSION COULD BE RECRUITED AS A WAY TO POTENTIATE CYTOTOXICITY OF IMATINIB AND TO ENHANCE THE THERAPEUTIC EFFICACY OF CML. HERE, WE PROPOSED FOR THE FIRST TIME THAT THE INHIBITORY EFFECT OF PANOBINOSTAT WAS OVERSHADOWED, AT LEAST PARTIALLY, THROUGH THE ABERRANT ACTIVATION OF THE PHOSPHOINOSITIDE 3-KINASE (PI3K)/C-MYC AXIS. MEANWHILE, WE FOUND THAT UPON BLOCKAGE OF AUTOPHAGY AND THE PROTEASOME PATHWAY, AS THE MAIN AXIS INVOLVED IN THE ACTIVATION OF AUTOPHAGY, THE ANTI-LEUKEMIC PROPERTY OF THE HDAC INHIBITOR WAS POTENTIATED. TAKEN TOGETHER, OUR STUDY SUGGESTS THE BENEFICIAL APPLICATION OF HDAC INHIBITION IN THE TREATMENT STRATEGIES OF CML; HOWEVER, FURTHER IN VIVO STUDIES ARE NEEDED TO DETERMINE THE EFFICACY OF THIS INHIBITOR, EITHER AS A SINGLE AGENT OR IN COMBINATION WITH SMALL MOLECULE INHIBITORS OF PI3K AND/OR C-MYC IN THIS MALIGNANCY. 2021