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Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

World Journal of Gastroenterology 2024年第19期30卷 2575-2602页

作者： Tian Peng Fang Sun Jia-Chun Yang Mei-Hong Cai Man-Xiu Huai Jia-Xing Pan Fei-Yu Zhang Lei-Ming Xu Department of Gastroenterology Xinhua Hospital Affiliated to Shanghai Jiao Tong UniversityShanghai 200092China

BACKGROUND Lactate,previously considered a metabolic byproduct,is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment.Further investigations confirmed that lactate is a primary regulator,introducing recently described post-translational modifications of histone and non-histone proteins,termed lysine lactylation.Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation.However,our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.AIM To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.METHODS RNA-seq and clinical data of pancreatic adenocarcinoma(PDAC)were obtained from the GTEx(Genotype-Tissue Expression)and TCGA(The Cancer Genome Atlas)databases via Xena Explorer,and GSE62452 datasets from GEO.Data on lactylation-related genes were obtained from publicly available sources.Differential expressed genes(DEGs)were acquired by using R package“DESeq2”in R.Univariate COX regression analysis,LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model.Further analyses,including functional enrichment,ESTIMATE,and CIBERSORT,were performed to analyze immune status and treatment responses in patients with pancreatic cancer.PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention;two PDAC cell lines with the most pronounced lactylation were selected.Subsequently,RT-PCR was employed to assess the expression of LRGs genes;SLC16A1,which showed the highest expression,was selected for further investigation.SLC16A1-mediated lactylation was analyzed by immunofluorescence,lactate production analysis,colony formation,transwell,and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells.In vivo validation was performed using an established tumor model.RESULTS In this study,we successfully identified 10 differentially e

关键词： Pancreatic adenocarcinoma lactylation Prognosis Immunotherapy Tumor microenvironment

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Microglia lactylation in relation to central nervous system diseases

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Neural Regeneration Research 2025年第1期20卷 29-40页

作者： Hui Yang Nan Mo Le Tong Jianhong Dong Ziwei Fan Mengxian Jia Juanqing Yue Ying Wang School of Pharmacy Hangzhou Normal UniversityHangzhouZhejiang ProvinceChina Department of Clinical Laboratory The Fourth Clinical Medical College of Zhejiang University of Traditional Chinese Medicine(Hangzhou First People’s Hospital)HangzhouZhejiang ProvinceChina College of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK Department of Orthopedics(Spine Surgery) the First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina Department of Pathology Affiliated Hangzhou First People’s HospitalWestlake University School of MedicineHangzhouZhejiang ProvinceChina Department of Clinical Research Center Affiliated Hangzhou First People’s HospitalWestlake University School of MedicineHangzhouZhejiang ProvinceChina

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

关键词： brain central nervous system glycolysis immune response inflammation lactate metabolism lactate lactylation microglia neurodegenerative diseases

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The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment

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Genes & Diseases 2023年第5期10卷 2029-2037页

作者： Yan Zhang Qiu Peng Jinhua Zheng Yuzhong Yang Xuemei Zhang Aiyu Ma Yuxia Qin Zailong Qin Xiang Zheng Department of Pathology Affiliated Hospital of Guilin Medical UniversityGuilinGuangxi 541001China Hunan Key Laboratory of Cancer Metabolism Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunan 410013China Laboratory of Genetics and Metabolism Maternal and Child Health Hospital of Guangxi Zhuang Autonomous RegionGuangxi Birth Defects Research and Prevention InstituteNanningGuangxi 530003China

Lactate is an end product of glycolysis.Owing to the lactate shuttle concept introduced in the early 1980s,increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis.Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells,resulting in diverse biological consequences including decreased lipolysis,immune regulation,and anti-inflammation wound healing,and enhanced exercise performance in association with the gut microbiome.Furthermore,increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones,which accounts for its key role in immune modulation and maintenance of homeostasis.Here,we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

关键词： Epigenetic regulation Lactate lactylation Microenvironment Tumorigenesis

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Histone lactylation promotes cell proliferation,migration and invasion through targeting HMGB1 in endometriosis

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The Journal of Biomedical Research 2023年第6期37卷 470-478页

作者： Jie Chen Pengfei Qin Yanli Sun Suping Han Department of Obstetrics and Gynecology Women's Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health Care HospitalNanjingJiangsu 210004China Department of Gynecology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210004China

Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity.However,the mechanism of endometriosis is still unclear.Lactate can be covalently modified to lysine residues of histones and other proteins,which is called lactylation.The results showed that the higher level of lactate and lactate dehydrogenase A enhanced the histone H3 lysine 18 lactylation(H3K18lac)in ectopic endometrial tissues and ectopic endometrial stromal cells than that in normal endometrial tissues and normal endometrial stromal cells.Lactate promoted cell proliferation,migration,and invasion in endometriosis.Mechanistically,lactate induced H3K18lac to promote the expression of high-mobility group box 1(HMGB1)in endometriosis,and HMGB1 knockdown significantly reduced the cell proliferation,migration,and invasion of the lactate-treated cells through the phosphorylation of AKT.In conclusion,lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1,which may provide a novel target for the prevention and treatment of endometriosis.

关键词： endometriosis ESCs lactate lactylation HMGB1

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Protein lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

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Genomics, Proteomics & Bioinformatics 2023年第6期21卷 1163-1181页

作者： Deqi Yin Ning Jiang Chang Cheng Xiaoyu Sang Ying Feng Ran Chen Qijun Chen Key Laboratory of Livestock Infectious Diseases in Northeast China Ministry of EducationKey Laboratory of ZoonosisCollege of Animal Science and Veterinary MedicineShenyang Agricultural UniversityShenyang 110166China The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites Chinese Academy of Medical SciencesShenyang 110866China

The biology of Toxoplasma gondii,the causative pathogen of one of the most widespread parasitic diseases(toxoplasmosis),remains poorly understood.Lactate,which is derived from glucose metabolism,is not only an energy source in a variety of organisms,including T.gondii,but also a regulatory molecule that participates in gene activation and protein function.Lysine lactylation(Kla)is a type of post-translational modifications(PTMs)that has been recently associated with chromatin remodeling;however,Kla of histone and non-histone proteins has not yet been studied in T.gondii.To examine the prevalence and function of lactylation in T.gondii parasites,we mapped the lactylome of proliferating tachyzoite cells and identified 1964 Kla sites on 955 proteins in the T.gondii RH strain.Lactylated proteins were distributed in multiple subcellular compartments and were closely related to a wide variety of biological processes,including mRNA splicing,glycolysis,aminoacyl-tRNA biosynthesis,RNA transport,and many signaling pathways.We also performed a chromatin immunoprecipitation sequencing(ChIP-seq)analysis using a lactylationspecific antibody and found that the histones H4K12la and H3K14la were enriched in the promoter and exon regions of T.gondii associated with microtubule-based movement and cell invasion.We further confirmed the delactylase activity of histone deacetylases TgHDAC2–4,and found that treatment with anti-histone acetyltransferase(TgMYST-A)antibodies profoundly reduced protein lactylation in T.gondii.This study offers the first dataset of the global lactylation proteome and provides a basis for further dissecting the functional biology of T.gondii.

关键词： Toxoplasmagondit lactylation Proteinpost-translational modification Metabolism ChIP-seq

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lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells

Lactylation-driven METTL3-mediated RNA m6A modification prom...

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第十四届全国免疫学学术大会

作者： Jia Xiong Jia He Jiongli Pan Weijie Liao Hongying Ye Qingqing Wang Institute of Immunology Zhejiang University

Tumor-infiltrating myeloid cells( TIMs) are crucial cell populations involved in tumor immune escape, and their immunosuppressive functions are regulated by multiple epigenetic mechanisms. RNA N-methyladenosine(mA) modification has been shown to regulate tumor progression. Our study revealed that RNA methyltransferase methyltransferase-like 3(METTL3) promotes mA modification of phosphokinase Janus kinase 1(JAK1) mRNA in TIMs. The mA-YTH N-methyladenosine RNA-binding protein 1( YTHDF1) axis enhances its protein translation efficiency in polysomes. JAK1 significantly contributes to the phosphorylation of the signal transducer and activator of transcription 3(STAT3) and further nuclear translocation, which potently initiates the transcription of downstream genes that are responsible for the immunosuppressive functions of TIMs. Furthermore, we found that lactate accumulated in the tumor microenvironment promotes the expression of METTL3 in TIMs in the form of histone H3K18 lactylation. Interestingly, we also identified two lactylation modification sites in the Cys-Cys-Cys-His(CCCH) zinc finger domain of METTL3 and this type of lysine lactylation is essential for the target recognition domain of METTL3 to capture target RNA. Taken together, our study reveals that lactylation-driven METTL3-mediated RNA mA modification promotes the immunosuppressive function of TIMs.

关键词： METTL3 m~6A Tumor-infiltrating myeloid cells lactate lactylation JAK-STAT

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Tumor metabolite lactate promotes tumorigenesis through regulating regulatory T cells by modulating Moesin lactylation and enhancing TGF-β signaling

Tumor metabolite lactate promotes tumorigenesis through regu...

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第十四届全国免疫学学术大会

作者： Jian Gu Jinren Zhou Ling Lu The first affiliated hospital of Nanjing Medical University

Tregs, which Foxp3 characterizes, play a vital role in maintaining immune homeostasis. Previous studies had revealed the critical role of Tregs in sustaining tumor microenvironment and accelerating tumorigenesis through suppressing T cell activation and immune surveillance. Several studies had shown that lactate is a crucial metabolite in cancer and relates to the tumor prognosis, metastases, and overall survival of patients. In this study, we focused on the impacts of lactate on Tregs. In vitro experiments showed that the lactate improved the stability and function of Tregs. Contrastly, the degradation of lactate reduced Treg induction, which increased anti-tumor immunity and decreased tumor growth in mice. Mechanism study showed that lactate modulated Tregs’ generation through lactylation, and four potential lactylation sites related to Tregs were selected, and antibodies for the lacylation site of the indicated protein were generated for each of these sites. Antagonist of Moesin Lys72 lactylation suppressed the effect of lactate on Tregs in vitro and reduced the generation of tumor in vivo. Structure analysis and TGF-β downstream signal examination discovered that the Lys72 lactylation of Moesin improved the interaction between Moesin and TGF-bRI, and downstream signaling of TGF-β. Besides, co-treatment of anti-PD-1 with lactate dehydrogenase inhibitor presented a more substantial anti-tumor effect comparing the anti-PD-1 alone group. Thus, we identified the underline mechanism of lactate as an essential small molecule in reinforcing Tregs in the tumor microenvironment through lactylation. Lactate and Moesin(or lactate) serves as a potential anti-cancer immunotherapeutic target.

关键词： Treg lactylation tumor Moesin

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