Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic t...Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.展开更多
Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its de...Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the classⅠhistone deacetylases(HDAC)exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein(TXNIP),causing reactive oxygen species(ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients’survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif(BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.展开更多
Angiogenesis,a process by which the preexisting blood vasculature gives rise to new capillary vessels,is associated with a variety of physiologic and pathologic conditions.However,the molecular mechanism underlying th...Angiogenesis,a process by which the preexisting blood vasculature gives rise to new capillary vessels,is associated with a variety of physiologic and pathologic conditions.However,the molecular mechanism underlying this important process remains poorly understood.Here we show that histone deacetylase 6(HDAC6),a microtubule-associated enzyme critical for cell motility,contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells.Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice.The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting.Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization.In addition,microtubule end binding protein 1(EB1)is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures.These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.展开更多
Melanoma differentiation-associated gene/interleukin-24(mda-7/IL-24)is a cytokine that can activate monocytes and T helper 2 cells.The expression of mda-7/IL-24 gradually fades with the progression of melanoma,and it ...Melanoma differentiation-associated gene/interleukin-24(mda-7/IL-24)is a cytokine that can activate monocytes and T helper 2 cells.The expression of mda-7/IL-24 gradually fades with the progression of melanoma,and it is undetectable at the metastatic stage.Ectopic expression of mda-7/IL-24 selectively suppresses growth and induces apoptosis in cancer cells with little harm to normal cells.However,the transcriptional regulation of the mda-7/IL-24 gene has not been extensively studied.In this study,we show that the expression of mda-7/IL-24 was upregulated by the histone deacetylase(HDAC)inhibitors trichostatin A(TSA)and sodium butyrate(NaBu),whereas it was downregulated by HDAC4.We also found that the histone acetylation level and the binding of the transcriptional factor Sp1 to the mad-7 promoter were reduced upon HDAC4 treatment.Moreover,the HDAC inhibitor TSA induced histone hyperacetylation and stimulated Sp1 binding to the mda-7/IL-24 promoter,which in turn enhanced the expression of mda-7/IL-24.Therefore,we conclude that histone acetylation modification plays an important role in the regulation of mda-7/IL-24 and that the transcription factor Sp1 participates in this process.展开更多
Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously fou...Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously found phosphodiesterase 4D(PDE4D)decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction.This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator.Overexpres-sion of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression,while the enrichment of histone deacetylase 1(HDAC1)was increased along with decreases in acetylated lysine 4(acH3K4)and 9(acH3K9)levels in the PDE4D promoter.HDAC1 overex-pression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels.Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI.EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 inter-actions and alleviate the reduction in PDE4D expression.Together,our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associ-ated histone deacetylation modification.Unlike the typical function of cTnI in cytoplasm,our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82225046,81821005,and 81903640)the Program of Shanghai Academic Research Leader(20XD1424800,China)。
文摘Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.
基金supported by the Multi-Year Research Grant of the University of Macao,China(MYRG2017-00176-FHS to Joong Sup Shim).
文摘Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the classⅠhistone deacetylases(HDAC)exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein(TXNIP),causing reactive oxygen species(ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients’survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif(BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.
基金the National Natural Science Foundation of China(Grant Nos.30825022 and 90913021)the Fok Ying Tung Education Foundation(Grant No.111036)the National Basic Research Program of China(Grant No.2007CB914802).
文摘Angiogenesis,a process by which the preexisting blood vasculature gives rise to new capillary vessels,is associated with a variety of physiologic and pathologic conditions.However,the molecular mechanism underlying this important process remains poorly understood.Here we show that histone deacetylase 6(HDAC6),a microtubule-associated enzyme critical for cell motility,contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells.Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice.The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting.Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization.In addition,microtubule end binding protein 1(EB1)is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures.These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.
基金This work was supported by grants from the National Natural Science Foundation of China(No.30671184)the Program for Changjiang Scholars and Innovative Research Team in University(No.IRT0519).
文摘Melanoma differentiation-associated gene/interleukin-24(mda-7/IL-24)is a cytokine that can activate monocytes and T helper 2 cells.The expression of mda-7/IL-24 gradually fades with the progression of melanoma,and it is undetectable at the metastatic stage.Ectopic expression of mda-7/IL-24 selectively suppresses growth and induces apoptosis in cancer cells with little harm to normal cells.However,the transcriptional regulation of the mda-7/IL-24 gene has not been extensively studied.In this study,we show that the expression of mda-7/IL-24 was upregulated by the histone deacetylase(HDAC)inhibitors trichostatin A(TSA)and sodium butyrate(NaBu),whereas it was downregulated by HDAC4.We also found that the histone acetylation level and the binding of the transcriptional factor Sp1 to the mad-7 promoter were reduced upon HDAC4 treatment.Moreover,the HDAC inhibitor TSA induced histone hyperacetylation and stimulated Sp1 binding to the mda-7/IL-24 promoter,which in turn enhanced the expression of mda-7/IL-24.Therefore,we conclude that histone acetylation modification plays an important role in the regulation of mda-7/IL-24 and that the transcription factor Sp1 participates in this process.
基金This study was supported by research grants from National Natural Science Foundation of China[grant number 81700214].
文摘Cardiac Troponin I(cTnI)is a subunit of the thin filament involved in regulation of heart contraction.Mutated cTnI accounts for most genetic mutations associated with restric-tive cardiomyopathy(RCM).We previously found phosphodiesterase 4D(PDE4D)decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction.This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator.Overexpres-sion of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression,while the enrichment of histone deacetylase 1(HDAC1)was increased along with decreases in acetylated lysine 4(acH3K4)and 9(acH3K9)levels in the PDE4D promoter.HDAC1 overex-pression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels.Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI.EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 inter-actions and alleviate the reduction in PDE4D expression.Together,our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associ-ated histone deacetylation modification.Unlike the typical function of cTnI in cytoplasm,our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.
