Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding o...Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.展开更多
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chem...The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.展开更多
Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis.Cancer cells reprogram their metabolism to meet the high bioenergetic and bios...Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis.Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation.Epigenetic dysregulation is a common fea-ture of human cancers,which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression.The epigenome is sensitive to metabolic changes.Metabolism produces various metabolites that are substrates,cofactors,or inhibitors of epigenetic enzymes.Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epige-netic landscape,inducing transcriptional responses to heterogeneous metabolic requirements.Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels.Epigenetic modifiers,chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism,facilitating malignant transformation.However,the significance of the close connection between metabolism and epi-genetics in the context of cancer has not been fully deciphered.Thus,it will be constructive to summarize and update the emerging new evidence support-ing this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options.In this review,we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aber-rations and metabolic rewiring to cancer initiation and development.Finally,we highlight the potential therapeutic opportunities for hematological malig-nancies and solid tumors by targeting this epigenetic-metabolic circuit.In summary,we endeavored to depict the current understanding of the coordi-nation between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.展开更多
Extrachromosomal circular DNA(eccDNA),ranging in size from tens to millions of base pairs,is independent of conventional chromosomes.Recently,eccDNAs have been considered an unanticipated major source of somatic rearr...Extrachromosomal circular DNA(eccDNA),ranging in size from tens to millions of base pairs,is independent of conventional chromosomes.Recently,eccDNAs have been considered an unanticipated major source of somatic rearrangements,contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome.In addition,the origin of eccDNA is considered to be associated with essential chromatin-related events,including the formation of super-enhancers and DNA repair machineries.Moreover,our understanding of the properties and functions of eccDNA has continuously and greatly expanded.Emerging investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes,such as epigenetic remodeling,telomere trimming,and the regulation of canonical signaling pathways.Importantly,its special distribution potentiates eccDNA as a measurable biomarker in many diseases,especially cancers.The loss of eccDNA homeostasis facilitates tumor initiation,malignant progression,and heterogeneous evolution in many cancers.An in-depth understanding of eccDNA provides novel insights for precision cancer treatment.In this review,we summarized the discovery history of eccDNA,discussed the biogenesis,characteristics,and functions of eccDNA.Moreover,we emphasized the role of eccDNA during tumor pathogenesis and malignant evolution.Therapeutically,we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.展开更多
Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of gen...Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.展开更多
An immunosuppressive state is a typical feature of the tumor microenvironment.Despite the dramatic success of immune checkpoint inhibitor(ICI)therapy in preventing tumor cell escape from immune surveillance,primary an...An immunosuppressive state is a typical feature of the tumor microenvironment.Despite the dramatic success of immune checkpoint inhibitor(ICI)therapy in preventing tumor cell escape from immune surveillance,primary and acquired resistance have limited its clinical use.Notably,recent clinical trials have shown that epigenetic drugs can significantly improve the outcome of ICI therapy in various cancers,indicating the importance of epigenetic modifications in immune regulation of tumors.展开更多
Background Diversified histone deacetylation inhibitors(HDACis)have demonstrated encouraging outcomes in multiple malignancies.N6-methyladenine(m6A)is the most prevalent messenger RNA modification that plays an essent...Background Diversified histone deacetylation inhibitors(HDACis)have demonstrated encouraging outcomes in multiple malignancies.N6-methyladenine(m6A)is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis.Howbeit,an in-depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains enigmatic.This study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular melanoma.Methods Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells.Dot blot assay was used to detect the global m6A RNA modification level.Multi-omics assays,including RNA-sequencing,cleavage under targets and tagmentation,single-cell sequencing,methylated RNA immunoprecipitation-sequencing(meRIP-seq),and m6A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing(miCLIP-seq),were performed to reveal the mechanisms of HDACis on methyltransferase-like 14(METTL14)and FAT tumor suppressor homolog 4(FAT4)in ocular melanoma.Quantitative real-time polymerase chain reaction(qPCR),western blotting,and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues.Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma.RNA-binding protein immunoprecipitation-qPCR,meRIP-seq,miCLIP-seq,and RNA stability assay were adopted to investigate the mechanism by which m6A levels of FAT4 were affected.Results First,we found that ocular melanoma cells presented vulnerability towards HDACis.HDACis triggered the elevation of m6A RNA modification in ocular melanoma.Further studies revealed that METTL14 served as a downstream candidate for HDACis.METTL14 was silenced by the hypo-histone acetylation status,whereas HDACi restored the normal histone acetylation level of METTL14,thereby inducing its expression.Subsequently,METTL14 served as a tumor suppressor by promoting the expression of FAT4,a tumor suppressor,in a m6A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner.Taken together,we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6A modification in tumorigenesis.Conclusions These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6A modification,which unveiling a“histone-RNA crosstalk”of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.展开更多
Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered on...Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.展开更多
Artificial intelligence(AI)is an emerging field in which computerized systems are used to carry out complex tasks in place of humans.Medical AI algorithms have been developed for disease diagnosis and prediction and t...Artificial intelligence(AI)is an emerging field in which computerized systems are used to carry out complex tasks in place of humans.Medical AI algorithms have been developed for disease diagnosis and prediction and treatment recommendation across various clinical data types,e.g.,chest X-rays,electrocardiograms,and other radiological images.1 In ophthalmology,particularly,great progress has been made in AI systems over the past decade.Color fundus photography(CFP)and optical coherence tomography(OCT),which are readily available in routine clinical practice,are both mainstream and useful retinal imaging modalities in ophthalmology.In September 2023,the 2023 Lasker-Debakey Clinical Medical Research Award was awarded to three scientists for their work on OCT for accurate retinal disease detection.展开更多
Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such...Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such as cancer.Specifically,lactate has been demonstrated to be pivotal in molding the tumor microenvironment(TME)through its effects on different cell populations.Within tumor cells,lactate impacts cell signaling pathways,augments the lactate shuttle process,boosts resistance to oxidative stress,and contributes to lactylation.In various cellular populations,the interplay between lactate and immune cells governs processes such as cell differentiation,immune response,immune surveillance,and treatment effectiveness.Furthermore,communication between lactate and stromal/endothelial cells supports basal membrane(BM)remodeling,epithelial-mesenchymal transitions(EMT),metabolic reprogramming,angiogenesis,and drug resistance.Focusing on lactate production and transport,specifically through lactate dehydrogenase(LDH)and monocarboxylate transporters(MCT),has shown promise in the treatment of cancer.Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy,leading to a synergistic therapeutic effect when combined with immunotherapy.The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism,highlighting the Heel of Achilles for cancer treatment.展开更多
dissemination to distant sites through a series of mechanisms,and it has been proved that lymph node metastasis(LNM)is an essential prognostic indicator in many different types of cancer.
Existing strategies for bone defect repair are difficult to monitor.Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring.Carbon nanotubes(C...Existing strategies for bone defect repair are difficult to monitor.Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring.Carbon nanotubes(CNT)have promising bioactivity and electrical conductivity.In this study,a noninvasive and intelligent monitoring scaffold was prepared for bone regeneration and monitoring by integrating carboxylated CNT into chemically cross-linked carboxymethyl chitosan hydrogel.CNT scaffold(0.5%w/v)demonstrated improved mechanical properties with good biocompatibility and electrochemical responsiveness.Cyclic voltammetry and electrochemical impedance spectroscopy of CNT scaffold responded sensitively to seed cell differentiation degree in both cellular and animal levels.Interestingly,the CNT scaffold could make up the easy deactivation shortfall of bone morphogenetic protein 2 by sustainably enhancing stem cell osteogenic differentiation and new bone tissue formation through CNT roles.This research provides new ideas for the development of noninvasive and electrochemically responsive bioactive scaffolds,marking an important step in the development of intelligent tissue engineering.展开更多
基金supported by grants from Shanghai Key Clinical Specialty,Shanghai Eye Disease Research Center(Grant No.:2022Zz01003 to Xianqun Fan)the National Key Research and Development Plan(Grant No.:2018YFC1106100 to Xianqun Fan)+1 种基金the National Natural Science Foundation of China(Grant Nos.:12275178 to Shengfang Ge and 82103240 to Peiwei Chai)Innovative Research Team of High-level Local Universities in Shanghai(Grant Nos.:SHSMU-ZDCX20210902 to Renbing Jia and SHSMUZDCX20210900 to Xianqun Fan),the Science and Technology Commission of Shanghai(Grant No.:19JC1410200 to Xianqun Fan),and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital,Shanghai Jiao Tong university School of Medicine(Grant No.:JYJC202210 to Ai Zhuang).
文摘Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
基金the Science and Technology Commission of Shanghai,China(Grant Nos.:20DZ2270800 and 19JC1410200)Innovative Research Team of High-Level Local Universities in Shanghai,China(Grant No.:SHSMU-ZDCX20210900)the National Natural Science Foundation of China(Grant No.:82073889).
文摘The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
基金National Natural Science Foundation of China,Grant/Award Number:81600766the Science and Technology Commission of Shanghai,Grant/Award Number:20DZ2270800Innovative research team of high-level local universities in Shanghai,Grant/Award Numbers:SHSMU-ZDCX20210900,SHSMU-ZDCX20210902。
文摘Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis.Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation.Epigenetic dysregulation is a common fea-ture of human cancers,which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression.The epigenome is sensitive to metabolic changes.Metabolism produces various metabolites that are substrates,cofactors,or inhibitors of epigenetic enzymes.Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epige-netic landscape,inducing transcriptional responses to heterogeneous metabolic requirements.Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels.Epigenetic modifiers,chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism,facilitating malignant transformation.However,the significance of the close connection between metabolism and epi-genetics in the context of cancer has not been fully deciphered.Thus,it will be constructive to summarize and update the emerging new evidence support-ing this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options.In this review,we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aber-rations and metabolic rewiring to cancer initiation and development.Finally,we highlight the potential therapeutic opportunities for hematological malig-nancies and solid tumors by targeting this epigenetic-metabolic circuit.In summary,we endeavored to depict the current understanding of the coordi-nation between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.
基金National Natural Science Foundation of China(grants 82103240,U1932135,81872339,82073889,and 81802702)Natural Science Foundation of Shanghai(20ZR1445600)+2 种基金China Postdoctoral Science Foundation Funded Project(2020M681328)Science and Technology Commission of Shanghai(grants 20DZ2270800 and 19JC1410200)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210902 and SHSMU-ZDCX20210900).
文摘Extrachromosomal circular DNA(eccDNA),ranging in size from tens to millions of base pairs,is independent of conventional chromosomes.Recently,eccDNAs have been considered an unanticipated major source of somatic rearrangements,contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome.In addition,the origin of eccDNA is considered to be associated with essential chromatin-related events,including the formation of super-enhancers and DNA repair machineries.Moreover,our understanding of the properties and functions of eccDNA has continuously and greatly expanded.Emerging investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes,such as epigenetic remodeling,telomere trimming,and the regulation of canonical signaling pathways.Importantly,its special distribution potentiates eccDNA as a measurable biomarker in many diseases,especially cancers.The loss of eccDNA homeostasis facilitates tumor initiation,malignant progression,and heterogeneous evolution in many cancers.An in-depth understanding of eccDNA provides novel insights for precision cancer treatment.In this review,we summarized the discovery history of eccDNA,discussed the biogenesis,characteristics,and functions of eccDNA.Moreover,we emphasized the role of eccDNA during tumor pathogenesis and malignant evolution.Therapeutically,we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.
基金supported by the Science and Technology Commission of Shanghai(20DZ2270800,China)the National Natural Science Foundation of China(grants 82073889)+1 种基金the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210900,China)China Postdoctoral Science Foundation(2022M722120,China)and Shanghai Sailing Program(22YF1422800,China)。
文摘Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.
基金supported by the Natural Science Foundation of China(NSFC 82000939)the Science and Technology Commission of Shanghai(20DZ2270800 and 22Y31900700).
文摘An immunosuppressive state is a typical feature of the tumor microenvironment.Despite the dramatic success of immune checkpoint inhibitor(ICI)therapy in preventing tumor cell escape from immune surveillance,primary and acquired resistance have limited its clinical use.Notably,recent clinical trials have shown that epigenetic drugs can significantly improve the outcome of ICI therapy in various cancers,indicating the importance of epigenetic modifications in immune regulation of tumors.
基金supported by the National Natural Science Foundation of China(82103240)the Science and Technology Commission of Shanghai(20DZ2270800,23ZR1438400,23ZR1480100 and 23YF1422400)+2 种基金Shanghai Key Clinical Specialty,Shanghai Eye Disease Research Center(2022ZZ01003)Cross-disciplinary Research Fund of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University(JYJC202210 and YG2023QNB15)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210900,SHSMUZDCX20210902).
文摘Background Diversified histone deacetylation inhibitors(HDACis)have demonstrated encouraging outcomes in multiple malignancies.N6-methyladenine(m6A)is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis.Howbeit,an in-depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains enigmatic.This study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular melanoma.Methods Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells.Dot blot assay was used to detect the global m6A RNA modification level.Multi-omics assays,including RNA-sequencing,cleavage under targets and tagmentation,single-cell sequencing,methylated RNA immunoprecipitation-sequencing(meRIP-seq),and m6A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing(miCLIP-seq),were performed to reveal the mechanisms of HDACis on methyltransferase-like 14(METTL14)and FAT tumor suppressor homolog 4(FAT4)in ocular melanoma.Quantitative real-time polymerase chain reaction(qPCR),western blotting,and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues.Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma.RNA-binding protein immunoprecipitation-qPCR,meRIP-seq,miCLIP-seq,and RNA stability assay were adopted to investigate the mechanism by which m6A levels of FAT4 were affected.Results First,we found that ocular melanoma cells presented vulnerability towards HDACis.HDACis triggered the elevation of m6A RNA modification in ocular melanoma.Further studies revealed that METTL14 served as a downstream candidate for HDACis.METTL14 was silenced by the hypo-histone acetylation status,whereas HDACi restored the normal histone acetylation level of METTL14,thereby inducing its expression.Subsequently,METTL14 served as a tumor suppressor by promoting the expression of FAT4,a tumor suppressor,in a m6A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner.Taken together,we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6A modification in tumorigenesis.Conclusions These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6A modification,which unveiling a“histone-RNA crosstalk”of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.
基金the National Natural Science Foundation of China(82200961)the National Basic Science Center Program of China(82388101)+2 种基金the Science and Technology Commission of Shanghai(20DZ2270800)Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology(2022SKLEKFKT004)the China Postdoctoral Science Foundation(2022M720091).
文摘Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.
基金This work was supported by the National Natural Science Foundation of China(82200961)the Science and Technology Commission of Shanghai(20DZ2270800)+1 种基金the Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology(2022SKLE-KFKT004)the China Postdoctoral Science Foundation(2022M720091,2023M741708,2023TQ0159,and GZC20233503)。
文摘Artificial intelligence(AI)is an emerging field in which computerized systems are used to carry out complex tasks in place of humans.Medical AI algorithms have been developed for disease diagnosis and prediction and treatment recommendation across various clinical data types,e.g.,chest X-rays,electrocardiograms,and other radiological images.1 In ophthalmology,particularly,great progress has been made in AI systems over the past decade.Color fundus photography(CFP)and optical coherence tomography(OCT),which are readily available in routine clinical practice,are both mainstream and useful retinal imaging modalities in ophthalmology.In September 2023,the 2023 Lasker-Debakey Clinical Medical Research Award was awarded to three scientists for their work on OCT for accurate retinal disease detection.
基金Supported by grants from the Science and Technology Commission of Shanghai(22Y31900700)Program of Innovative Research Team of High‑Level Local Universities in Shanghai(SHSMU‑ZDCX20210902)+1 种基金Shanghai Municipal Health Commission(2022YQ01)“New Star of Medical College”Young Medical Talents Training Program in Shanghai in 2020.
文摘Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings,particularly in intricate conditions such as cancer.Specifically,lactate has been demonstrated to be pivotal in molding the tumor microenvironment(TME)through its effects on different cell populations.Within tumor cells,lactate impacts cell signaling pathways,augments the lactate shuttle process,boosts resistance to oxidative stress,and contributes to lactylation.In various cellular populations,the interplay between lactate and immune cells governs processes such as cell differentiation,immune response,immune surveillance,and treatment effectiveness.Furthermore,communication between lactate and stromal/endothelial cells supports basal membrane(BM)remodeling,epithelial-mesenchymal transitions(EMT),metabolic reprogramming,angiogenesis,and drug resistance.Focusing on lactate production and transport,specifically through lactate dehydrogenase(LDH)and monocarboxylate transporters(MCT),has shown promise in the treatment of cancer.Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy,leading to a synergistic therapeutic effect when combined with immunotherapy.The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism,highlighting the Heel of Achilles for cancer treatment.
基金This work was jointly supported by the National Natural Science Foundation of China(Nos.82072567)the Foundation of Shanghai Ninth People's Hospital(Nos.YBKB202112).
文摘dissemination to distant sites through a series of mechanisms,and it has been proved that lymph node metastasis(LNM)is an essential prognostic indicator in many different types of cancer.
基金supported by the National Natural Science Foundation of China(81972530,62171275,82000879)the National Key R&D Project(2018YFC1106100 and 2018YFC1106101)+1 种基金Fund for Excellent Young Scholars of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine(JYYQ001)the Science and Technology Commission of Shanghai(20DZ2270800).
文摘Existing strategies for bone defect repair are difficult to monitor.Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring.Carbon nanotubes(CNT)have promising bioactivity and electrical conductivity.In this study,a noninvasive and intelligent monitoring scaffold was prepared for bone regeneration and monitoring by integrating carboxylated CNT into chemically cross-linked carboxymethyl chitosan hydrogel.CNT scaffold(0.5%w/v)demonstrated improved mechanical properties with good biocompatibility and electrochemical responsiveness.Cyclic voltammetry and electrochemical impedance spectroscopy of CNT scaffold responded sensitively to seed cell differentiation degree in both cellular and animal levels.Interestingly,the CNT scaffold could make up the easy deactivation shortfall of bone morphogenetic protein 2 by sustainably enhancing stem cell osteogenic differentiation and new bone tissue formation through CNT roles.This research provides new ideas for the development of noninvasive and electrochemically responsive bioactive scaffolds,marking an important step in the development of intelligent tissue engineering.
基金supported by the National Basic Science Center Program of China(82388101)the National Natural Science Foundation of China(82200961 and 82203260)+2 种基金the Science and Technology Commission of Shanghai(20DZ2270800)Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology(2022SKLEKFKT004)China Postdoctoral Science Foundation(2022M720091)。
