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EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway

Acta Pharmaceutica Sinica B 2024年第3期14卷 1187-1203页

作者： Yongyun Li Tianyu Zhu Jie Yang Qianqian Zhang Shiqiong Xu Shengfang Ge renbing jia jianming Zhang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200001China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200001China National Research Center for Translational Medicine(Shanghai) State Key Laboratory of Medical GenomicsShanghai Institute of HematologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Institute of Translational Medicine Zhangjiang Institute for Advanced StudyShanghai Jiao Tong UniversityShanghai 200240China

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 *** 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 ***,elevated expression of EHMT2 had been validated in UM ***,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T *** immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of *** transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA *** constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic *** 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 *** 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.

关键词： Uveal melanoma EHMT2 RhoA pathway ARHGAP29 G protein GNAQ GNA11

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Classification and treatment of orbital venous malformations: an updated review

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Frontiers of Medicine 2019年第5期13卷 547-555页

作者： Tianyuan Li renbing jia Xianqun Fan Department of Ophthalmology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of MedicineShanghai 200011China

Orbital venous malformation (OVM) is a congenital vascular disease. As a common type of vascular malformation in the orbit, OVM may result in vision deterioration and cosmetic defect. Classification of orbital vascular malformations, especially OVMs, is carried out on the basis of different categories, such as angiogenesis, hemodynamics, and locations. Management of OVM is complicated and challenging. Treatment approaches include sclerotherapy, laser therapy, embolization, surgical resection, and radiotherapy. A satisfactory outcome can be achieved only by selecting the appropriate treatment according to lesion characteristics and following the sequential multi-method treatment strategy. This article summarizes the current classification and treatment advances in OVM.

关键词： orbit venous malformation treatment sclerotherapy laser embolization

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Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs

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Journal of Pharmaceutical Analysis 2023年第2期13卷 127-141页

作者： Qili Liao Jie Yang Shengfang Ge Peiwei Chai jiayan Fan renbing jia Department of Ophthalmology Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200001China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai200001China

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome *** dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune ***,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple *** this review,we have updated recent understandings of KMTs'functions and the development of their targeted ***,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune *** addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT *** summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

关键词： Cancer Epigenetics Histone lysine methyltransferase Epigenetic inhibitors Combined therapeutic strategy Clinical application

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Epigenetic drug library screening reveals targeting DOT1L abrogates NAD^(+)synthesis by reprogramming H3K79 methylation in uveal melanoma

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Journal of Pharmaceutical Analysis 2023年第1期13卷 24-38页

作者： Xiang Gu Yu Hua Jie Yu Ludi Yang Shengfang Ge renbing jia Peiwei Chai Ai Zhuang Xianqun Fan Department of Ophthalmology Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in *** histone methylation contributes to the abnormal transcriptome during ***,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains ***,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 ***,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in *** 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 ***,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))***,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of ***,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.

关键词： Histone methylation Metabolic reprogramming Uveal melanoma Transcriptional addiction

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Crosstalk between metabolic reprogramming and epigenetics in cancer:updates on mechanisms and therapeutic opportunities

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Cancer Communications 2022年第11期42卷 1049-1082页

作者： Tongxin Ge Xiang Gu renbing jia Shengfang Ge Peiwei Chai Ai Zhuang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011P.R.China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200011P.R.China

Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of *** cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous *** dysregulation is a common fea-ture of human cancers,which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene *** epigenome is sensitive to metabolic *** produces various metabolites that are substrates,cofactors,or inhibitors of epigenetic *** 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 *** metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional *** modifiers,chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism,facilitating malignant ***,the significance of the close connection between metabolism and epi-genetics in the context of cancer has not been fully ***,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 *** 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 ***,we highlight the potential therapeutic op

关键词： cancer epigenetics metabolic reprogramming RNA epigenetics therapy

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Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m^(6)A RNA methylation in ocular melanoma

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Cancer Communications 2023年第11期43卷 1185-1206页

作者： Ai Zhuang Xiang Gu Tongxin Ge Shaoyun Wang Shengfang Ge Peiwei Chai renbing jia Xianqun Fan Department of Ophthalmology Shanghai Ninth People's HospitalShanghai JiaoTong University School of MedicineShanghaiP. R. China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology ShanghaiP. R. China

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 ***,an in-depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains *** study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular *** Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma *** blot assay was used to detect the global m6A RNA modification ***-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 *** 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 *** models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular ***-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 *** First,we found that ocular melanoma cells presented vulnerability towards *** triggered the elevation of m6A RNA modification in ocular *** studies revealed that METTL14 served as a downstream candidate for ***14 was silenced by the hypo-histone acetylation status,whereas HDACi restored the normal histone acetylation level of MET

关键词： epigenetics histone deacetylation inhibitors melanoma N6-methyladenine histone-RNA crosstalk

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A novel MYCN-YTHDF1 cascade contributes to retinoblastoma tumor growth by eliciting m^(6)A-dependent activation of multiple oncogenes

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中国科学:生命科学英文版 2023年第9期66卷 2138-2151页

作者： Yingxiu Luo Mengjia He Jie Yang Feifei Zhang Jie Chen Xuyang Wen jiayan Fan Xianqun Fan Peiwei Chai renbing jia Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai 200023China

Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even *** addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine(m^(6)A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m^(6)A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m^(6)A bindingdependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their m RNAs and enhancing m RNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.

关键词： MYCN YTHDF1 m^(6)A CDK5R1 retinoblastoma

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Cucurbitacin B-induced G2/M cell cycle arrest of conjunctival melanoma cells mediated by GRP78-FOXM1-KIF20A pathway

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3861-3876页

作者： Jinlian Wei Xin Chen Yongyun Li Ruoxi Li Keting Bao Liang Liao Yuqing Xie Tiannuo Yang Jin Zhu Fei Mao Shuaishuai Ni renbing jia Xiaofang Xu jian Li State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell MetabolismFrontiers Science Center for Materiobiology and Dynamic ChemistryShanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan College of PharmacyDali UniversityDali 671000China Clinical Medicine Scientific and Technical Innovation Center Shanghai Tenth People’s HospitalTongji University School of MedicineShanghai 200092China Key Laboratory of Tropical Biological Resources of Ministry of Education College of PharmacyHainan UniversityHaikou 570228China

Conjunctival melanoma(CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B(CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16,CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a Kdvalue of0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

关键词： Conjunctival melanoma Cucurbitacin B Activity-based protein profiling G2/M cell cycle GRP78 FOXM1 KIF20A Rare tumor

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我国眼肿瘤专业70年发展和展望

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中华眼科杂志 2020年第9期56卷 646-652页

作者：范先群贾仁兵上海交通大学医学院附属第九人民医院眼科上海市眼眶病眼肿瘤重点实验室200011

眼肿瘤包括眼内、眼眶、结膜、眼睑和泪器肿瘤,是一类可致死、致盲、致残的重要眼科疾病。70载栉风沐雨,我国眼肿瘤专业历经从无到有、从小到大的发展过程,取得累累硕果。尤其进入21世纪以来,我国眼肿瘤专业的发展进入快行道,基于生物... 详细信息

眼肿瘤包括眼内、眼眶、结膜、眼睑和泪器肿瘤,是一类可致死、致盲、致残的重要眼科疾病。70载栉风沐雨,我国眼肿瘤专业历经从无到有、从小到大的发展过程,取得累累硕果。尤其进入21世纪以来,我国眼肿瘤专业的发展进入快行道,基于生物样本库和动物模型阐明眼肿瘤发生机制;基于多中心队列研究和治疗新技术创建诊疗新模式;基于学术组织建设和国际交流,提高团队的学术能力和学科发展水平。展望未来,我国眼肿瘤专业将依托国家战略和科技创新,在基因检测和早期诊断、基础研究和靶向药物、学科交叉和智能诊疗、临床研究和转化医学等方面砥砺前行,进一步提高眼肿瘤患者的生存率、保眼率和生活质量。谨以此文祝贺《中华眼科杂志》创刊70周年。

关键词：眼肿瘤诊疗模式医师回顾性研究

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FGFR1特异性拮抗剂SU5402抑制人源晶状体上皮细胞增生的研究

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眼科研究 2009年第10期27卷 870-873页

作者：徐庆贾仁兵上海交通大学医学院附属第九人民医院眼科 200011 上海建工医院眼科 200083

目的本研究探讨体外应用碱性成纤维细胞生长因子(bFGF)受体1(FGFR1)特异性拮抗剂SU5402抑制人源晶状体上皮细胞(LECs)增生的影响。方法光镜下观察传代培养的永生化人源LEC-B3细胞的形态,用αB-晶状体蛋白免疫组织化学法鉴定其性质。采... 详细信息

目的本研究探讨体外应用碱性成纤维细胞生长因子(bFGF)受体1(FGFR1)特异性拮抗剂SU5402抑制人源晶状体上皮细胞(LECs)增生的影响。方法光镜下观察传代培养的永生化人源LEC-B3细胞的形态,用αB-晶状体蛋白免疫组织化学法鉴定其性质。采用逆转录聚合酶链反应(RT-PCR)法检测LEC-B3细胞中bFGF和FGFR1的mRNA表达。在传代培养、融合度为70%的LEC-B3细胞中加入SU5402(20μg/mL),以磷酸盐缓冲液(PBS)作为对照,2 d后用流式细胞术(FCM)检测LEC-B3细胞中细胞增生核抗原(PCNA)的表达。结果传代培养的LEC-B3细胞呈多边形上皮样生长,表达特异性的αB-晶状体蛋白;LEC-B3细胞中bFGF和FGFR1的mRNA表达量与内参甘油醛-3-磷酸脱氢酶(GAPDH)相当;LEC-B3细胞中PCNA阳性细胞的比例,SU5402实验组为(23.95±7.82)%,PBS对照组为(58.86±15.43)%,差异有统计学意义(P<0.01)。结论LEC-B3细胞丰富表达bFGF和FGFR1的mRNA;体外应用SU5402可显著抑制LEC-B3增生,有望成为防治后囊膜混浊(PCO)的有效方法。

关键词：后囊膜混浊碱性成纤维细胞生长因子成纤维细胞生长因子受体晶状体上皮细胞-B3 成纤维细胞生长因子受体拮抗剂 SU5402

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