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Natural products as LSD1 inhibitors for cancer therapy

Acta Pharmaceutica Sinica B 2021年第3期11卷 621-631页

作者： Yuan Fang Chao Yang Zhiqiang Yu Xiaochuan Li Qingchun Mu Guochao Liao Bin Yu Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China Institute of Innovation&Application Zhejiang Ocean UniversityZhoushcm 316022China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China The People’s Hospital of Gaozhou Gaozhou 525200China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase1(LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

关键词： epigenetic regulation Histone demethylase Natural products LSD1 inhibitors Drug discovery Cancer therapy

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O-linked β-N-acetylglucosamine modification and its biological functions

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Science Bulletin 2015年第12期60卷 1055-1061,I0002页

作者： Yan Liu Shaojun Dai Lijing Xing Yunyuan Xu Kang Chong Alkali Soil Natural Environmental Science Center NortheastForestry University Key Laboratory of Saline-Alkali VegetationEcology Restoration in Oil Field Ministry of Education Harbin150040 China Key Laboratory of Plant Molecular Physiology Institute ofBotany Chinese Academy of Sciences Beijing 100093 China

The covalent attachment of O-linked β-N- acetylglucosamine （O-GIcNAc） to Ser/Thr residues of proteins acts as not only a posttranslational modification but also a nutritional sensor in nucleus and cytoplasm, which directly regulates the expression of genes and multiple crucial signal transduction pathways. Dynamic O- GlcNAcylation at Ser/Thr residues is catalyzed by two key enzymes, O-GIcNAc transferase （OGT） and O-GlcNAcase, which are responsible for addition and removal of the O- GlcNAc modification, respectively. O-GlcNAc modifica- tion plays important roles in cellular signaling in animals, especially in human diseases. Two orthologs of OGT in plants, SECRET AGENT and SPINDLY, have been reported to be involved in diverse plant processes. However, compared with the functional mechanisms revealed in animals, the consequences of protein O-GlcNAc modifi- cation in plants is largely unknown, and the relationship between O-GlcNAcylation and cellular processes needs to be explored. In this review, we summarized the recent advances on O-GlcNAc modification and its biological functions in animals and plants, and prospect of more special functions of O-GlcNAc will be revealed in plants.

关键词： O-GlcNAc Posttranslational modification epigenetic regulation Plants

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Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation

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Neuroscience Bulletin 2022年第4期38卷 359-372页

作者： Yan-Yan Wu Hai-Long Zhang Xiaomin Lu Han Du Yong-Chang Li Ping-An Zhang Guang-Yin Xu Jiangsu Key Laboratory of Neuropsychiatric Diseases Institute of NeuroscienceSoochow UniversitySuzhou 215123China Department of Oncology The Affiliated Haian Hospital of Nantong UniversityNantong 226600China Center for Translational Medicine The Affiliated Zhangjiagang Hospital of Soochow UniversitySuzhou 215600China

Irritable bowel syndrome is a gastrointestinal disorder of unknown etiology characterized by widespread,chronic abdominal pain associated with altered bowel *** amounts of evidence indicate that injury and inflammation during the neonatal period have long-term effects on tissue structure and function in the adult that may predispose to gastrointestinal *** this study we aimed to investigate how the epigenetic regulation of DNA demethylation of the p2x7r locus guided by the transcription factor GATA binding protein 1(GATA1)in spinal astrocytes affects chronic visceral pain in adult rats with neonatal colonic inflammation(NCI).The spinal GATA1 targeting to DNA demethylation of p2x7r locus in these rats was assessed by assessing GATA1 function with luciferase assay,chromatin immunoprecipitation,patch clamp,and interference in vitro and in *** addition,a decoy oligodeoxynucleotide was designed and applied to determine the influence of GATA1 on the DNA methylation of a p2x7r CpG *** showed that NCI caused the induction of GATA1,Ten-eleven translocation 3(TET3),and purinergic receptors(P2X7Rs)in astrocytes of the spinal dorsal horn,and demonstrated that inhibiting these molecules markedly increased the pain threshold,inhibited the activation of astrocytes,and decreased the spinal sEPSC *** also markedly demethylated the p2x7r locus in a manner dependent on the enhancement of both a GATA1–TET3 physical interaction and GATA1 binding at the p2x7r ***,we showed that demethylation of the p2x7r locus(and the attendant increase in P2X7R expression)was reversed upon knockdown of GATA1 or TET3 expression,and demonstrated that a decoy oligodeoxynucleotide that selectively blocked the GATA1 binding site increased the methylation of a CpG island in the p2x7r *** results demonstrate that chronic visceral pain is mediated synergistically by GATA1 and TET3 via a DNA-demethylation mechanism that controls p2x7r trans

关键词： Chronic visceral pain GATA binding protein 1 Ten-eleven translocation 3 Purinergic receptor epigenetic regulation Spinal astrocytes

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epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

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Acta Pharmaceutica Sinica B 2020年第5期10卷 723-733页

作者： Xi Chen Xiaohui Pan Wenxin Zhang Hongjie Guo Shuyuan Cheng Qiaojun He Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Immunotherapy strategies targeting the programmed cell death ligand 1(PD-L1)/programmed cell death 1(PD-1)pathway in clinical treatments have achieved remarkable success in treating multiple types of ***,owing to the heterogeneity of tumors and individual immune systems,PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many *** evidence has shown that an effective response to anti-PD-Ll/anti-PD-1 therapy requires establishing an integrated immune *** in any step of the immune cycle is one of the most important causes of immunotherapy *** in the immune cycle can be restored by epigenetic modification,including reprogramming the environment of tumor-associated immunity,eliciting an immune response by increasing the presentation of tumor antigens,and by regulating T cell trafficking and ***,a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

关键词： epigenetic regulation Immune cycle PD-L1PD-1 blockade Cancer Immunotherapy

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High auxin stimulates callus through SDG8-mediated histone H3K36 methylation in Arabidopsis

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Journal of Integrative Plant Biology 2022年第12期64卷 2425-2437页

作者： Jun Ma Qiang Li Lei Zhang Sen Cai Yuanyuan Liu Juncheng Lin Rongfeng Huang Yongqiang Yu Mingzhang Wen Tongda Xu College of Life Sciences Fujian Agriculture and Forestry UniversityFuzhou 350002China Plant Synthetic Biology Center FAFU-UCR Joint Center for Horticultural Biology and MetabolomicsHaixia Institute of Science and TechnologyFujian Agriculture and Forestry UniversityFuzhou 350002China Shanghai Center for Plant Stress Biology CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 201602China Basic Forestry and Proteomics Research Center Haixia Institute of Science and TechnologyFujian Agricuture and Forestry UniversityFuzhou 350002China Frontiers Science Center for Synthetic Biology(Ministry of Education) Tianin UniversityTianjin 300072China

Callus induction,which results in fate transition in plant cells,is considered as the first and key step for plant *** process can be stimulated in different tissues by a callus-inducing medium(CIM),which contains a high concentration of phytohormone *** a few key regulators for callus induction have been identified,the multiple aspects of the regulatory mechanism driven by high levels of auxin still need further ***,we find that high auxin induces callus through a H3 K36 histone methylation-dependent mechanism,which requires the methyltransferase SET DOMAIN GROUP 8(SDG8).During callus induction,the increased auxin accumulates SDG8 expression through a TIR1/AFBs-based transcriptional ***8 then deposits H3 K36 me3 modifications on the loci of callus-related genes,including a master regulator WOX5 and the cell proliferation-related genes,such as *** epigenetic regulation in turn is required for the transcriptional activation of these genes during callus *** findings suggest that the massive transcriptional reprogramming for cell fate transition by auxin during callus formation requires epigenetic modifications including SDG8-mediated histone H3 K36 *** results provide insight into the coordination between auxin signaling and epigenetic regulation during fundamental processes in plant development.

关键词： auxin callus formation epigenetic regulation H3K36 methylation SDG8 TIR1/AFBs

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Control of Leaf Senescence by an MeOH- Jasmonates Cascade that Is epigenetically Regulated by OsSRT1 in Rice

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Molecular Plant 2016年第10期9卷 1366-1378页

作者： ChuanYing Fang Hua Zhang Jian Wan YangYang Wu Kang Li Cheng Jin Wei Chen ShouChuang Wang WenSheng Wang HaiWei Zhang Pan Zhang Fei Zhang LiangHuan Qu Xianqing Liu Dao-Xiu Zhou Jie Luo National Key Laboratory of Crop Genetic Improvement and National Center of Plant Gene Research (Wuhan) Huazhong Agricultural University Wuhan 430070China Institute for Nutritional Sciences Shanghai Institutes for Biological Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai200031 China College of Life Science and Technology Huazhong Agricultural University Wuhan 430070 China Institute of Plant Sciences Paris-Saclay Universite Paris-sud 11 Orsay 91405 France

Although considerable progress has been made in identifying the genes regulating accumulation of hormones that are involved in leaf senescence, only a few studies have focused on natural variations in jasmonates content and much less on the underlying genetic basis. Moreover, the epigenetic regulation of jasmonate-mediated leaf senescence remains largely unknown, in this study, we carried out metabolic profiling of a worldwide collection of rice accessions and demonstrated that there are substantial variations in jasmonate levels among these accessions. A subsequent metabolite-based genornewide association study identified candidates for two major quantitative genes （QTGs）, OsPME1 and OsTSD2, affecting the content of jasmonates. Further investigations using a series of relevant mutants and transgenic lines revealed the MeOH-jasmonata cascade plays an important role in regulating leaf senescence. Moreover, we showed that OsSRT1, one of the two Sir2 （silent information regugator 2） homologs in rice, negatively regulates leaf senescence by repressing expression of the biosynthetic genes of this metabolic cascade and at least particiaUy through histone H3K9 deacetylation of OsPME1. Taken together, our results indicate that the MeOH-jasmonates cascade and its epigenetic regulation are crucial for controlling leaf senescence process in rice.

关键词： MeOH-jasmonate cascade leaf senescence natural variation epigenetic regulation

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PHF20 collaborates with PARP1 to promote stemness and aggressiveness of neuroblastoma cells through activation of SOX2 and OCT4

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Journal of Molecular Cell Biology 2018年第2期10卷 147-160页

作者： Wenyong Long Wei Zhao Bo Ning Jing Huang Junjun Chu Linfeng Li Qianquan Ma Changsheng Xing Helen Y. Wang Qing Liu Rong-Fu Wang Department of Neurosurgery in Xiangya Hospital Central South University Changsha 410008 China Center for inflammation and epigenetics Houston Methodist Research Institute Houston TX 77030 USA Key Laboratory of Stem Cells and Tissue Engineering Ministry of Education Zhongshan School of Medicine Sun Yat-sen University Guangzhou 510080 China Institute Center for Molecular Design and Biomimetics The Biodesign Institute Arizona State University Tempe AZ 85287 USA Department of Microbiology and Immunology WeiU Cornell Medicine Cornell University New York NY 10065 USA Institute of Biosciences and Technology Texas A&M University Health Science Center Houston TX 77030 USA

The differentiation status of neuroblastoma （NB） strongly correlates with its clinical outcomes; however, the molecular mechanisms driving maintenance of sternness and differentiation remain poorly understood. Here, we show that plant homeodomain finger-containing protein 20 （PHF20） functions as a critical epigenetic regulator in sustaining stem cell-like phenotype of NB by using CRISPR/Casg-based targeted knockout （KO） for high-throughput screening of gene function in NB cell differentiation. The expression of PHF20 in NB was significantly associated with high aggressiveness of the tumor and poor outcomes for NB patients. Deletion of PHF20 inhibited NB cell proliferation, invasive migration, and stem ceU-Uke traits. Mechanistically, PHF20 interacts with poly（ADP-ribose） polymerase 1 （PARP1） and directly binds to promoter regions of octamer-binding transcription factor 4 （OCT4） and sex determining region Y-box 2 （SOX2） to modulate a histone mark associated with active transcription, trimethylation of lysine 4 on histone H3 protein subunit （H3K4me3）. Overexpression of OCT4 and SOX2 restored growth and progression of PHF20 KO tumor cells. Consistently, OCT4 and SOX2 protein levels in clinical NB specimens were positively correlated with PHF20 expression. Our results establish PHF20 as a key driver of NB stem cell-like properties and aggressive behaviors, with implications for prognosis and therapy.

关键词： PHF20 neuroblastoma PARP1 cancer stem cell-like traits epigenetic regulation

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Chromatin remodeling factors regulate environmental stress responses in plants

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Journal of Integrative Plant Biology 2021年第3期63卷 438-450页

作者： Ze-Ting Song Jian-Xiang Liu Jia-Jia Han Yunnan Key Laboratory of Plant Reproductive Adaptation and Evolutionary Ecology Yunnan UniversityKunming 650500China State Key Laboratory of Plant Physiology and Biochemistry College of Life SciencesZhejiang UniversityHangzhou 310027China Laboratory of Ecology and Evolutionary Biology State Key Laboratory for Conservation and Utilization of Bio‐Resources in YunnanYunnan UniversityKunming 650500China

Environmental stress from climate change and agricultural activity threatens global plant biodiversity as well as crop yield and *** sessile organisms,plants must maintain the integrity of their genomes and adjust gene expression to adapt to various environmental *** eukaryotes,nucleosomes are the basic unit of chromatin around which genomic DNA is packaged by *** enable dynamic access to packaged DNA,eukaryotes have evolved Snf2(sucrose nonfermenting 2)family proteins as chromatin remodeling factors(CHRs)that modulate the position of nucleosomes on *** plant stress responses,CHRs are recruited to specific genomic loci,where they regulate the distribution or composition of nucleosomes,which in turn alters the accessibility of these loci to general transcription or DNA damage repair ***,CHRs interplay with other epigenetic mechanisms,including DNA methylation,histone modifications,and deposition of histone *** are also involved in RNA processing at the posttranscriptional *** this review,we discuss major advances in our understanding of the mechanisms by which CHRs function during plants’response to environmental stress.

关键词： chromatin remodeling environmental stress epigenetic regulation replication stress stress responses

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Long noncoding RNA(lncRNA)H19:An essential developmental regulator with expanding roles in cancer,stem cell differentiation,and metabolic diseases

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Genes & Diseases 2023年第4期10卷 1351-1366页

作者： Junyi Liao Bowen Chen Zhenglin Zhu Chengcheng Du Shengqiang Gao Guozhi Zhao Piao Zhao Yonghui Wang Annie Wang Zander Schwartz Lily Song Jeffrey Hong William Wagstaff Rex CHaydon Hue HLuu Jiaming Fan Russell RReid Tong-Chuan He Lewis Shi Ning Hu Wei Huang Departments of Orthopedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Research Center Chongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA The Medical Scientist Training Program The University of Chicago Pritzker School of MedicineChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene *** one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and ***,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or ***,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic *** discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of ***,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

关键词： Cancer epigenetic regulation H19 LncRNA Long-noncoding RNA Metabolic diseases Stem cell differentiation

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CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain

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Neuroscience Bulletin 2023年第6期39卷 947-961页

作者： Ting Xu Zhen-Yu Li Meng Liu Su-Bo Zhang Huan-Huan Ding Jia-Yan Wu Su-Yan Lin Jun Liu Jia-You Wei Xue-Qin Zhang Wen-Jun Xin Neuroscience Program of Zhongshan School of Medicine and the Fifth Affiliated Hospital Sun Yat-sen UniversityGuangzhou510080China Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-sen UniversityGuangzhou510120China Department of Anesthesia and Pain Medicine Guangzhou First People’s HospitalGuangzhou510000China Department of Physiology Xuzhou Medical UniversityXuzhou221004China Department of Neurology The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou510000China Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong Provincial Key Laboratory of Biomedical Imagingand Department of Interventional MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityZhuhai519000China The Affiliated Brain Hospital(Guangzhou Huiai Hospital)and School of Health Management Guangzhou Medical UniversityGuangzhou510182China Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Guangzhou510000China

Effective treatments for neuropathic pain are lacking due to our limited understanding of the *** circRNAs are mainly enriched in the central nervous ***,their function in various physiological and pathological conditions have yet to be ***,we identified circFhit,an exon-intron circRNA expressed in GABAergic neurons,which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic ***,we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R^(+) neurons by promoting the expression of its parental gene Fhit in ***,circFhit was directly bound to the intronic region of Fhit,and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit *** summary,we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R^(+) neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

关键词： Chronic pain Neuropathic pain CircRNA Inhibitory transmission epigenetic regulation

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