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Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization

National Science Review 2022年第5期9卷 119-128页

作者： Jin-Tao Li Kai-Yue Li Ying Su Yuan Shen Ming-Zhu Lei Fan Zhang Miao Yin Zheng-Jun Chen Wen-Yu Wen Wei-Guo Hu Dan Su Jia Qu Qun-Ying Lei Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Cancer Institutes Key Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Medical EpigeneticsInternational Co-Laboratory of Medical Epigenetics and MetabolismMinistry of Science and Technology Shanghai Medical College Fudan University State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell ScienceChinese Academy of Sciences Cancer Research Institute Zhejiang Cancer Hospital and Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province Department of Oncology Shanghai Medical College Fudan University State Key Laboratory of Medical neurobiology Fudan University

BCAT2-mediated branched-chain amino acid（BCAA） catabolism is critical for pancreatic ductal adenocarcinoma（PDAC） development,especially at an early ***,whether a high-BCAA diet promotes PDAC development in vivo,and the underlying mechanism of BCAT2 upregulation,remain ***,we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia（PanIN）progression in LSL-KrasG12 D/+; Pdx1-Cre（KC） ***,we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 ***,BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in *** importantly,USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice ***,a positive correlation between USP1 and BCAT2 is found in KC;LSL-KrasG12D/+;p53flox/+;Pdx1-Cre mice and clinical ***,a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

关键词： USP1 deubiquitylation BCAT2 PanIN PDAC

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Rewiring local immune milieu by boosting dendritic cell for pancreatic cancer treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1445-1446页

作者： Yifan Zhang Qun-Ying Lei Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences Cancer InstitutesKey Laboratory of Breast Cancer in ShanghaiThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghaiChina Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina State Key Laboratory of Medical neurobiology Fudan UniversityShanghaiChina

A recent article by Hedge et al.(Cancer Cell 37,289–307.e289,2020)demonstrated that decreased dendritic cell and elevated Th17 cell could explain the immunosuppressive environment of PDAC when compared with that in lung *** DC population using Flt3L and CD40 agonist showed improved efficacy on PDAC mouse models and shed new light on its immunotherapeutic strategies.

关键词： al elevated lung

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Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1769-1777页

作者： Ming-Zhu Lei Xu-Xu Li Ye Zhang Jin-Tao Li Fan Zhang Yi-Ping Wang Miao Yin Jia Qu Qun-Ying Lei Department of Biochemistry and Molecular Biology School of Basic Medical SciencesShanghai Medical CollegeFudan University131 Dong’an RoadShanghai 200032China Cancer Metabolism Laboratory and the Shanghai Key Laboratory of Medical epigenetics the International Co-laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesShanghai Medical CollegeFudan University131 Dong’an RoadShanghai 200032China Cancer Institute Fudan University Shanghai Cancer Center and Department of OncologyShanghai Medical CollegeFudan University270 Dong’an RoadShanghai 200032China State Key Laboratory of Medical neurobiology Fudan University131 Dong’an RoadShanghai 200032China

Pancreatic ductal adenocarcinoma(PDAC)is well-known for inefficient early diagnosis,with most patients diagnosed at advanced *** evidence indicates that elevated plasma levels of branched-chain amino acids(BCAAs)are associated with an increased risk of pancreatic ***-chain amino acid transaminase 2(BCAT2)is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain ***,we show that BCAT2 is acetylated at lysine 44(K44),an evolutionarily conserved ***2 acetylation leads to its degradation through the ubiquitin–proteasome pathway and is stimulated in response to BCAA ***-responsive element-binding(CREB)-binding protein(CBP)and SIRT4 are the acetyltransferase and deacetylase for BCAT2,*** and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA *** importantly,the K44R mutant promotes BCAA catabolism,cell proliferation,and pancreatic tumor ***,the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.

关键词： BCAA elevated diagnosis

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Cancer metabolism and dietary interventions

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Cancer Biology & Medicine 2022年第2期19卷 163-174页

作者： Lin Qian Fan Zhang Miao Yin Qunying Lei Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences Cancer InstitutesKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyShanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghai 200030China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200030China State Key Laboratory of Medical neurobiology Fudan UniversityShanghai 200030China Lead Contact Shanghai 200030China

Metabolic remodeling is a key feature of cancer *** of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells,the so-called Warburg *** cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal ***,targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical *** particular,the management of nutrient availability is becoming more attractive in cancer *** this review,we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor ***,we present a comprehensive overview of changes in macronutrient ***,amino acids,and lipids,are rewired in the cancer microenvironment individually or ***,we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.

关键词： Cancer metabolism diet intervention carbohydrate amino acid lipid

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A paternal protein facilitates sperm RNA delivery to regulate zygotic development

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Science China(Life Sciences) 2023年第10期66卷 2342-2353页

作者： Dongdong Li Shijing Huang Yongping Chai Ruiqian Zhao Jing Gong Qiangfeng Cliff Zhang Guangshuo Ou Wenyu Wen Tsinghua-Peking Center for Life Sciences Beijing Frontier Research Center for Biological StructureMcGovern Institute for Brain ResearchSchool of Life Sciences and MOE Key Laboratory for Protein ScienceTsinghua UniversityBeijing 100084China Department of Neurosurgery Huashan Hospitalthe Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceNational Center for Neurological DisordersSchool of Basic Medical SciencesFudan UniversityShanghai 200032China

Sperm contributes essential paternal factors,including the paternal genome,centrosome,and oocyte-activation signals,to sexual ***,it remains unresolved how sperm contributes its RNA molecules to regulate early embryonic ***,we show that the Caenorhabditis elegans paternal protein SPE-11 assembles into granules during meiotic divisions of spermatogenesis and later matures into a perinuclear structure where sperm RNAs *** reconstitute an SPE-11 liquid-phase scaffold in vitro and find that SPE-11 condensates incorporate the nematode RNA,which,in turn,promotes SPE-11 phase *** of SPE-11 does not affect sperm motility or fertilization but causes pleiotropic development defects in early embryos,and spe-11 mutant males reduce m RNA levels of genes crucial for an oocyte-to-embryo transition or embryonic *** results reveal that SPE-11 undergoes phase separation and associates with sperm RNAs that are delivered to oocytes during fertilization,providing insights into how a paternal protein regulates early embryonic development.

关键词： SPE-11 phase separation paternal factor early embryonic development

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Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism

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Journal of Molecular Cell Biology 2022年第4期14卷 39-50页

作者： Fan Zhangi: Di Wangl- intao Li Ying Su Suling Liu Qun-Ying Lei Miao Yin Fudan University Shanghai Cancer Center Instutes of Biomedical Science&School fasic Medical Sciences CancerlnstesKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CllegeFudan UniversityShanghai 200032China State Key Laboratory of Medical neurobiology Fudan UniversityShanghai 20o032China

Folate metabolism plays an essential role in tumor *** cancers display therapeutic response to reagents targeting key enzymes of the folate cycle,but obtain chemoresistance ***,novel targets in folate metabolism are highly *** dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2(MTHFD2)is one of the key enzymes in folate metabolism and its expression is highly increased in mutiple human ***,the underlying mechanism that regulates MTHFD2 expression remains ***,we elucidate that SIRT4 deacetylates the conserved lysine 50(K50)residue in MTHFD2.K50 deacetylation destabilizes MTHFD2 by elevating cullin 3 E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation,leading to suppression of nicotinamide adenine dinucleotide phosphate production in tumor cells and accumulation of intracellular reactive oxygen species,which in turn inhibits the growth of breast cancer ***,our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability,bridging nutrient/folate stress and cellular redox to act on cancer cell growth.

关键词： folate metabolism MTHFD2 CUL3 SIRT4 acetylation breast cancer

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Metabolic regulation of innate immunity in cancer immunotherapy

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Cancer Biology & Medicine 2023年第12期20卷 898-902页

作者： Yuheng Liao Hui Yang Department of Neurosurgery Huashan HospitalShanghai Key Laboratory of Medical EpigeneticsInternational Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesInstitute for Translational Brain ResearchShanghai Medical College of Fudan UniversityShanghai 200032China Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghai 200032China State Key Laboratory of Medical neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghai 200032China

Innate immunity,originally recognized as the primary defense mechanism against pathogenic infections,has also been shown to have an important role in anti-tumor *** cells recognize cytosolic DNA and RNA,which triggers a cascade of signaling events via nucleic-acid sensing receptors,including endosomal Toll-like receptors(TLRs),cytoplasmic cyclic GMP-AMP synthase(cGAS)for double-stranded DNA sensing,and cytoplasmic retinoic acid-inducible gene I(RIG-I)for double-stranded RNA detection.

关键词： immunity immunotherapy Metabolic

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Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

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Science China(Life Sciences) 2022年第10期65卷 2017-2030页

作者： Xuan Pei Kai-Yue Li Yuan Shen Jin-Tao Li Ming-Zhu Lei Cai-Yun Fang Hao-Jie Lu Hui-Juan Yang Wenyu Wen Miao Yin Jia Qu Qun-Ying Lei Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences Cancer InstitutesKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Gynecological Oncology Fudan University Shanghai Cancer CenterShanghai 200032China State Key Laboratory of Medical neurobiology Fudan UniversityShanghai 200032China

Epithelial ovarian cancer(EOC) exhibits strong dependency on the tricarboxylic acid(TCA) cycle and oxidative phosphorylation to fuel anabolic ***,we show that malate dehydrogenase 2(MDH2),a key enzyme of the TCA cycle,is palmitoylated at cysteine 138(C138) residue,resulting in increased activity of *** next identify that ZDHHC18 acts as a palmitoyltransferase of *** deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and ***2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in ***,re-expression of wild-type MDH2,but not its palmitoylation-deficient C138 S mutant,sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer ***,MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian *** observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer,yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

关键词： EOC MDH2 cysteine palmitoylation ZDHHC18 glutamine

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Proteins moonlighting in tumor metabolism and epigenetics

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Frontiers of Medicine 2021年第3期15卷 383-403页

作者： Lei Lv Qunying Lei MOE Key Laboratory of Metabolism and Molecular Medicine Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesFudan UniversityShanghai 200032China Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences Cancer InstitutesKey Laboratory of Breast Cancer in ShanghaiThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China State Key Laboratory of Medical neurobiology Fudan UniversityShanghai 200032China

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor *** plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer *** respond to nutrient stress and to meet the requirements for rapid cell proliferation,cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for *** actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic *** signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

关键词： moonlighting function tumor metabolism epigenetics

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Harnessing innate immune pathways for therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun Hao Lin Yuheng Liao Hui Yang Ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China Institute for Translational Brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State Key Laboratory of Medical neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Medical epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer *** pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal *** targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical ***,to date,the clinical success of drugs targeting the innate immune pathway remains ***,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor *** uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate *** this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell *** propose that within the TME,the innate immune pathway exhibits multidimensional *** diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling *** pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative *** our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs therapeutic innate

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