Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerat...Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane.The presence of NI was positively associated with patient survival.The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival.Methods:We examined NI in 72 paraffin-embedded specimens of HCC.Immunohistochemistry(IHC)and immunofluorescence(IF)were performed to investigate the content and shape of NI.β-catenin gene(CTNNB1)mutations were analyzed by next generation sequencing.Results:We detected the accumulation ofβ-catenin and glutamine synthetase(a target gene ofβ-catenin)proteins within NI.Further,we found immunopositivity for the lysine demethylase KDM2A in NI.KDM2A is known to be involved inβ-catenin degradation.We detected significant associations between the presence ofβ-catenin and autophagy-associated proteins in NI.Double-IF revealed co-localization ofβ-catenin and p62 in the same NI.Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival.Conclusion:We detected accumulations ofβ-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion.Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI.展开更多
The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive.Long non-coding RNAs(lncRNAs)have emerged as essential cell fate regulators.Here we found LncKdm2b(also ...The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive.Long non-coding RNAs(lncRNAs)have emerged as essential cell fate regulators.Here we found LncKdm2b(also known as Kancr),a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b,is transiently expressed during early differentiation of cortical projection neurons.Interestingly,Kdm2b’s transcription is positively regulated in cis by LncKdm2b,which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2b’s promoter by associating with hnRNPAB.Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons.These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.展开更多
IL-6 plays important and pleiotropic roles in infection and inflammatory diseases,and its production needs to be tightly regulated.However,the epigenetic mechanism underlying Il6 gene transcription remains to be fully...IL-6 plays important and pleiotropic roles in infection and inflammatory diseases,and its production needs to be tightly regulated.However,the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated.Here,we report that lysine-specific demethylase 2b(KDM2B),which demethylates H3K4me3 and H3K36me2,is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α,IL-1,and IFN-β.Compared to wild-type mice,KDM2B-deficient mice were more resistant to endotoxin shock and colitis,with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera.KDM2B selectively bound the Il6 promoter but did not alter histone demethylation;instead,KDM2B interacted with Brahma-related gene 1(Brg1),the core ATPase subunit of SWI/SNF chromatin remodeling complexes,to facilitate chromatin accessibility of the Il6 promoter.Furthermore,KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription.Thus,our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.展开更多
Epigenetic regulators have been implicated in tumorigenesis of many types of cancer;however,their roles in endothelial cell cancers such as canine hemangiosarcoma(HSA)have not been studied.In this study,we find that l...Epigenetic regulators have been implicated in tumorigenesis of many types of cancer;however,their roles in endothelial cell cancers such as canine hemangiosarcoma(HSA)have not been studied.In this study,we find that lysine-specific demethylase 2 b(KDM2 B)is highly expressed in HSA cell lines compared with normal canine endothelial cells.Silencing of KDM2 B in HSA cells results in increased cell death in vitro compared with the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage.Similarly,doxycycline-induced KDM2 B silencing in tumor xenografts results in decreased tumor sizes compared with the control.Furthermore,KDM2 B is also highly expressed in clinical cases of HSA.We hypothesize that pharmacological KDM2 B inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA.We treat HSA cells with GSK-J4,a histone demethylase inhibitor,and find that GSK-J4 treatment also induces apoptosis and cell death.In addition,GSK-J4 treatment decreases tumor size.Therefore,we demonstrate that KDM2 B acts as an oncogene in HSA by enhancing the DNA damage response.Moreover,we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.展开更多
文摘Aim:β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer.Recently,we detected intranuclear inclusions(NI)in hepatocellular carcinoma(HCC)containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane.The presence of NI was positively associated with patient survival.The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival.Methods:We examined NI in 72 paraffin-embedded specimens of HCC.Immunohistochemistry(IHC)and immunofluorescence(IF)were performed to investigate the content and shape of NI.β-catenin gene(CTNNB1)mutations were analyzed by next generation sequencing.Results:We detected the accumulation ofβ-catenin and glutamine synthetase(a target gene ofβ-catenin)proteins within NI.Further,we found immunopositivity for the lysine demethylase KDM2A in NI.KDM2A is known to be involved inβ-catenin degradation.We detected significant associations between the presence ofβ-catenin and autophagy-associated proteins in NI.Double-IF revealed co-localization ofβ-catenin and p62 in the same NI.Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival.Conclusion:We detected accumulations ofβ-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion.Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI.
基金supported by grants from National Key R&D Program of China(2018YFA0800700)National Natural Science Foundation of China(Grant Nos.31671418 and 31471361)+2 种基金National Natural Science Foundation of Hubei Province(2018CFA016)Fundamental Research Funds for the Central Universities(2042017kf0242)Wuhan University Experiment Technology Project Funding(WHU-2018-SYJS-01).
文摘The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive.Long non-coding RNAs(lncRNAs)have emerged as essential cell fate regulators.Here we found LncKdm2b(also known as Kancr),a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b,is transiently expressed during early differentiation of cortical projection neurons.Interestingly,Kdm2b’s transcription is positively regulated in cis by LncKdm2b,which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2b’s promoter by associating with hnRNPAB.Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons.These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.
基金We thank X.Sun and M.Jin for technical assistance.This work was supported by the National Natural Science Foundation of China(31570871,81571541,81771695,31770970,and 81770094)Program of Shanghai Chief Scientist of Medical and Health Subject(2018BR16)Shuguang Program sponsored by the Shanghai Education Development Foundation and Shanghai Municipal Education Commission(18SG33).
文摘IL-6 plays important and pleiotropic roles in infection and inflammatory diseases,and its production needs to be tightly regulated.However,the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated.Here,we report that lysine-specific demethylase 2b(KDM2B),which demethylates H3K4me3 and H3K36me2,is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α,IL-1,and IFN-β.Compared to wild-type mice,KDM2B-deficient mice were more resistant to endotoxin shock and colitis,with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera.KDM2B selectively bound the Il6 promoter but did not alter histone demethylation;instead,KDM2B interacted with Brahma-related gene 1(Brg1),the core ATPase subunit of SWI/SNF chromatin remodeling complexes,to facilitate chromatin accessibility of the Il6 promoter.Furthermore,KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription.Thus,our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.
基金supported by the Sasakawa Scientific Research Grant(KG,Research No.2019-4111)provided by the Japan Science Society and the KAKENHI Grant-in-Aid for Young Scientist(KA,Number 18K14575,20K15654)provided by Japan Society for the Promotion of Science。
文摘Epigenetic regulators have been implicated in tumorigenesis of many types of cancer;however,their roles in endothelial cell cancers such as canine hemangiosarcoma(HSA)have not been studied.In this study,we find that lysine-specific demethylase 2 b(KDM2 B)is highly expressed in HSA cell lines compared with normal canine endothelial cells.Silencing of KDM2 B in HSA cells results in increased cell death in vitro compared with the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage.Similarly,doxycycline-induced KDM2 B silencing in tumor xenografts results in decreased tumor sizes compared with the control.Furthermore,KDM2 B is also highly expressed in clinical cases of HSA.We hypothesize that pharmacological KDM2 B inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA.We treat HSA cells with GSK-J4,a histone demethylase inhibitor,and find that GSK-J4 treatment also induces apoptosis and cell death.In addition,GSK-J4 treatment decreases tumor size.Therefore,we demonstrate that KDM2 B acts as an oncogene in HSA by enhancing the DNA damage response.Moreover,we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.
