The p60 subunit of the chromatin assembly factor-1 complex,that is,chromatin assembly factor-1 subunit B(CHAF1B),is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self...The p60 subunit of the chromatin assembly factor-1 complex,that is,chromatin assembly factor-1 subunit B(CHAF1B),is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal.CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy.However,its expression and clinical significance in lung squamous-cell carcinoma(LUSC)remain unclear.In this study,we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates.Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes.Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo.Furthermore,bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7(SETD7)as a significant CHAF1B target gene.In addition,CHAF1B competitively binds to the SETD7 promoter region and represses its transcription.Altogether,these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.展开更多
Noise-induced hearing loss(NIHL)is primarily driven by inflammatory processes within the cochlea,where noise exposure triggers the activation of the NOD-like receptor protein 3(NLRP3)inflammasome,leading to an inflamm...Noise-induced hearing loss(NIHL)is primarily driven by inflammatory processes within the cochlea,where noise exposure triggers the activation of the NOD-like receptor protein 3(NLRP3)inflammasome,leading to an inflammatory cascade.The interaction between increased NLRP3 expression and NF-κB activity can further amplify cochlear inflammation.Our findings reveal that(R)-PFI-2 hydrochloride,a selective inhibitor of the SETD7 enzyme,effectively inhibits the activation of the cochlear NF-κB pathway,suppresses the release of proinflammatory factors,and prevents inflammasome assembly.This intervention disrupts the perpetuating cycle of inflammation,thereby alleviating damage to cochlear hair cells attributed to acoustic trauma.Consequently,(R)-PFI-2 hydrochloride emerges as a promising pharmacological candidate for NIHL,targeting and moderating the excessive immune and inflammatory responses implicated in the pathology of hearing loss.展开更多
基金supported by the National Key Research and Development Program of China(Nos.2022YFA1103900 and 2020YFA0803300)CAMS Initiative for Innovative Medicine(Nos.2021-1-I2M-012,2021-I2M-1-014,2022-I2M-2-001,2021-I2M-1-021,and 2022-I2M-1-009)+1 种基金the Non-Profit Central Research Institute Fund of CAMS(Nos.2022-RC310-05 and 2021-RC310-003)the National Natural Science Foundation of China(Nos.82372944,82073092,and 82273076).
文摘The p60 subunit of the chromatin assembly factor-1 complex,that is,chromatin assembly factor-1 subunit B(CHAF1B),is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal.CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy.However,its expression and clinical significance in lung squamous-cell carcinoma(LUSC)remain unclear.In this study,we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates.Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes.Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo.Furthermore,bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7(SETD7)as a significant CHAF1B target gene.In addition,CHAF1B competitively binds to the SETD7 promoter region and represses its transcription.Altogether,these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.
基金supported by the Science and Technology Development Project of Xuzhou Science and Technology Bureau(KC21249)Science and Technology Development Project of Chongqing(CSTB2022NSCQ-M SX1598)+2 种基金Science and Technology Development Project of Xiaogan(XGKJ2023010010)Scientific Research Startup Foundation of Hainan UniversityScience and Technology Development Project of Hainan.
文摘Noise-induced hearing loss(NIHL)is primarily driven by inflammatory processes within the cochlea,where noise exposure triggers the activation of the NOD-like receptor protein 3(NLRP3)inflammasome,leading to an inflammatory cascade.The interaction between increased NLRP3 expression and NF-κB activity can further amplify cochlear inflammation.Our findings reveal that(R)-PFI-2 hydrochloride,a selective inhibitor of the SETD7 enzyme,effectively inhibits the activation of the cochlear NF-κB pathway,suppresses the release of proinflammatory factors,and prevents inflammasome assembly.This intervention disrupts the perpetuating cycle of inflammation,thereby alleviating damage to cochlear hair cells attributed to acoustic trauma.Consequently,(R)-PFI-2 hydrochloride emerges as a promising pharmacological candidate for NIHL,targeting and moderating the excessive immune and inflammatory responses implicated in the pathology of hearing loss.
