Journal of Experimental & Clinical Cancer Research最新文献

{"title":"PD-1⁺ NK cell subsets in high grade serous ovarian cancer: an indicator of disease severity and a target for combined immune-checkpoint blockade.","authors":"Marco Greppi, Giovanna Tabellini, Ornella Patrizi, Valentina Obino, Matteo Bozzo, Mariangela Rutigliani, Franco Gorlero, Martina Di Luca, Laura Paleari, Ombretta Melaiu, Michele Paudice, Fabrizio Loiacono, Patrizio Castagnola, Valerio Gaetano Vellone, Pascale André, Domenico Mavilio, Gianluca Ubezio, Simona Candiani, Camilla Jandus, Lorenzo Moretta, Andrea De Censi, Daniel Olive, Simona Sivori, Eric Vivier, Fabio Rampinelli, Silvia Parolini, Silvia Pesce, Emanuela Marcenaro","doi":"10.1186/s13046-025-03508-2","DOIUrl":"https://doi.org/10.1186/s13046-025-03508-2","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"258"},"PeriodicalIF":12.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.","authors":"Arturo Orlacchio, Yasuko Kajimura, Lara Rizzotto, Anna Tessari, Shimaa H A Soliman, Rosa Visone, Liwen Zhang, Brian Fries, Lino Tessarollo, Joseph Amann, David P Carbone, Alessia Lodi, Amer Ahmed, Ruggiero Gorgoglione, Giuseppe Fiermonte, Mike Freitas, Dario Palmieri, Jacob Kaufman, Vincenzo Coppola","doi":"10.1186/s13046-025-03491-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03491-8","url":null,"abstract":"<p><strong>Background: </strong>RANBP9 and RANBP10, also called Scorpins, are essential components of the C-terminal to LisH (CTLH) complex, an evolutionarily conserved poorly investigated multisubunit E3 ligase. Their role in non-small cell lung cancer (NSCLC) is unknown.</p><p><strong>Methods: </strong>In this study, first we used stable loss-of function and overexpression inducible cell lines to investigate the ability of either RANBP9 or RANBP10 to form their own functional CTLH complex. Then, we probed lysates from patient tumors and analyzed data from publicly available repositories to investigate the expression of RANBP9 and RANBP10. Finally, we used inducible cell lines in vitro to recapitulate the expression observed in patients and investigate the changes of the proteome and the ubiquitylome associated with either RANBP9 or RANBP10 in NSCLC.</p><p><strong>Results: </strong>Here, we show that the two Scorpins are both expressed in NSCLC cells and that either of them can independently support the formation of the CTLH complex. Short-term experiments revealed that the RANBP9 and RANBP10 proteins balance each other in terms of expression, and the acute overexpression of one or the other results in significant reshaping of the NSCLC cell proteome and ubiquitylome. A higher RANBP9/RANBP10 ratio is associated with greater proliferation in both NSCLC cell lines and patients. Acute increased expression of RANBP10 slows NSCLC cell proliferation and decreases the level of proliferation-associated proteins, including key players in DNA replication.</p><p><strong>Conclusions: </strong>We present evidence that the Scorpins act as partial antagonists and work together as one sophisticated rheostat to modulate the CTLH complex ubiquitylation output, which regulates cell proliferation and other key biological processes in NSCLC. These results suggest that the two Scorpins can be considered as targets for the treatment of NSCLC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"259"},"PeriodicalIF":12.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAP1 expression elicits pro-tumoral functions in macrophages associated to malignant peripheral nerve sheath tumor cells.","authors":"Francesca Scantamburlo, Alessia Rubini, Margherita Toffanin, Maria Egle Castorina, Francesco Ciscato, Sofia Tomasoni, Paolo Finotti, Ranieri Verin, Valentina Zappulli, Marco Fantuz, Camilla Bean, Andrea Rasola, Ionica Masgras","doi":"10.1186/s13046-025-03525-1","DOIUrl":"https://doi.org/10.1186/s13046-025-03525-1","url":null,"abstract":"<p><strong>Background: </strong>Metabolic adaptations can sustain the pro-neoplastic functions exerted by macrophages in the tumor microenvironment. Malignant peripheral nerve sheath tumors (MPNSTs), aggressive and incurable sarcomas that develop either sporadically or in the context of the genetic syndrome Neurofibromatosis type 1, are highly infiltrated by macrophages, whose contribution to MPNST growth remains poorly characterized. Here, we analyze the role played by the molecular chaperone TRAP1, a regulator of mitochondrial metabolic pathways, in shaping the pro-tumoral activity of macrophages associated to MPNST cells.</p><p><strong>Methods: </strong>We have studied the phenotypic changes elicited by a MPNST cell-conditioned medium in macrophages with or without TRAP1, and their subsequent ability to support MPNST cell growth and migration and endothelial cell angiogenesis.</p><p><strong>Results: </strong>The presence of TRAP1 is required in both naive and M2-like macrophages for eliciting phenotypic changes that lead to the acquisition of pro-neoplastic features. TRAP1-expressing macrophages become able to sustain MPNST cell growth and migration and to exert pro-angiogenic properties on endothelial cells through accumulation of the metabolite succinate and the ensuing activation of a HIF-1α-dependent transcriptional program.</p><p><strong>Conclusions: </strong>Our data provide evidence of a molecular crosstalk between MPNST cellular components, in which soluble factors released by cancer cells drive phenotypic changes in macrophages that in turn enhance pro-tumoral biological routines in both MPNST and endothelial cells. TRAP1-dependent metabolic rewiring in macrophages is mandatory for sustaining this interplay, as a TRAP1-succinate-HIF-1α signaling axis orchestrates their acquisition of tumor-promoting features.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"257"},"PeriodicalIF":12.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma.","authors":"Federica Torricelli, Benedetta Donati, Veronica Manicardi, Mila Gugnoni, Francesca Reggiani, Gloria Manzotti, Pierluigi Di Chiaro, Cristian Ascione, Simonetta Piana, Riccardo Valli, Roberto Piro, Massimiliano Paci, Nicola Facciolongo, Filippo Lococo, Alessia Ciarrocchi","doi":"10.1186/s13046-025-03522-4","DOIUrl":"https://doi.org/10.1186/s13046-025-03522-4","url":null,"abstract":"<p><strong>Introduction: </strong>Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.</p><p><strong>Methods: </strong>A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.</p><p><strong>Results: </strong>CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.</p><p><strong>Conclusion: </strong>These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"256"},"PeriodicalIF":12.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel SOX6 + melanoma cell subtype promotes early microsatellite invasion in Asian acral melanoma through fatty acid transport disorder.","authors":"Chuan Lv, Kexin Chen, Tengjiao Wang, Junfeng Jiang, Guanghui Hu, Jianan Gu, Tao Liu, Sheng Wang, Haiying Dai, Yue Wang","doi":"10.1186/s13046-025-03516-2","DOIUrl":"https://doi.org/10.1186/s13046-025-03516-2","url":null,"abstract":"<p><p>Acral melanoma (AM) is the predominant subtype of melanoma in Asians. Early detection and prevention can significantly improve patient outcomes; however, there is a lack of effective early biomarkers for predicting AM metastasis. Here, we employed single-cell and spatial transcriptomics analyses to investigate early microsatellite lesions of AM and identify biomarkers of invasiveness in these lesions. Our results characterize a highly immunosuppressive microenvironment and metabolic process shifts in early AM microsatellite lesions that promote the metastatic potential. The transcription factor SOX6 is overexpressed in microsatellite lesions and marks a population of highly invasive melanoma cells. The pro-invasive role of overexpressed SOX6 was validated in vivo and in vitro, including its ability to enhance tumor invasion by upregulating cellular glycolysis, disrupt fatty acid transport, and increase intracellular phosphatidylcholine content. This study suggests that SOX6-overexpressing melanoma cells are the main driver subpopulation promoting early invasion of AM and establishes SOX6 and fatty acid transport processes as biomarkers and potential therapeutic targets for early melanoma metastasis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"254"},"PeriodicalIF":12.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vinburnine potentiates anti-PD1 immunotherapy in melanoma through IL-24 secretion via P38/MAPK/ATF3 signaling.","authors":"Susi Zhu, Xu Zhang, Waner Liu, Zhe Zhou, Siyu Xiong, Xiang Chen, Cong Peng","doi":"10.1186/s13046-025-03521-5","DOIUrl":"https://doi.org/10.1186/s13046-025-03521-5","url":null,"abstract":"<p><strong>Background: </strong>Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses.</p><p><strong>Methods: </strong>This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases.</p><p><strong>Results: </strong>This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8⁺ T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches.</p><p><strong>Conclusions: </strong>These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"255"},"PeriodicalIF":12.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional tumor-reactive CD8 + T cells in pancreatic cancer.","authors":"Hongwei Sun, Changying Shi, Guoqing Fang, Qiufang Guo, Zhengliang Du, Geer Chen, Yasong Wu, Zhe-Sheng Chen, Jian Hua, Yan Zhang, Zhiwen Shi","doi":"10.1186/s13046-025-03517-1","DOIUrl":"https://doi.org/10.1186/s13046-025-03517-1","url":null,"abstract":"<p><strong>Background: </strong>Traditional methods for detecting tumor-reactive (TR) CD8 + tumor-infiltrating lymphocytes (TILs) in pancreatic cancer usually focus on neo-antigenic epitopes, which is limited by the narrow range of antigenic epitopes, and the lengthy and complex identification processes, resulting in an incomplete understanding of the biological characteristics of TR CD8 + TILs.</p><p><strong>Methods: </strong>This study introduces a novel approach that integrates single-cell sequencing with deep learning (DL), which enables the identification of tumor-reactive CD8 + T cells without neoantigen screening. The T Cell Receptor Engineered T (TCR-T) cell tumor organoid killing model was employed to validate the functionality of DL-identified TR CD8 + T cells, while spatial transcriptomics was used to confirm receptor-ligand interactions involving TR CD8 + TILs.</p><p><strong>Results: </strong>Comprehensive analyses of TR CD8 + TILs revealed impaired mitochondrial respiratory chain-related pathways regulated by the transcription factor FOS. The TIGIT-NECTIN2 axis was identified as an important immune checkpoint molecule in the tumor microenvironment of pancreatic cancer. T cell receptor (TCR) repertoire analysis demonstrated that some TR CD8 + TILs possess multiple TCR αβ combinations. Furthermore, TCR-T targeting experiments using tumor organoids revealed that combinations of multiple distinct TR TCRs exhibit significantly superior tumor-killing capabilities compared to a single type TCR. Clinically, a higher proportion of TR CD8 + TILs was positively associated with improved responses to neoadjuvant immunotherapy and longer overall survival in pancreatic cancer patients.</p><p><strong>Conclusion: </strong>This study represents a significant advancement in the understanding of TR TIL biology and provides a rapid and accurate method to identify TR CD8 TILs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"253"},"PeriodicalIF":12.8,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy resistance in non-small cell lung cancer: from mechanisms to therapeutic opportunities.","authors":"Huiyu Wang, Xiaomin Niu, Zhenning Jin, Shaoxing Zhang, Rong Fan, Hua Xiao, Shen S Hu","doi":"10.1186/s13046-025-03519-z","DOIUrl":"https://doi.org/10.1186/s13046-025-03519-z","url":null,"abstract":"<p><p>This review provides a comprehensive synthesis of current knowledge on immunotherapy resistance in non-small cell lung cancer (NSCLC), a disease that accounts for approximately 85% of all lung cancer cases and remains the leading cause of cancer-related death worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved survival for a subset of patients with advanced NSCLC, over 70% of cases ultimately exhibit primary or acquired resistance, underscoring the urgent need to understand the underlying mechanisms. The review categorizes resistance into tumor-intrinsic and tumor-extrinsic processes and provides an in-depth mechanistic analysis of how factors such as tumor antigen loss, impaired antigen presentation, cGAS-STING pathway dysregulation, metabolic reprogramming in tumor microenvironment (TME), immune cell exhaustion, and microbiomes collectively contribute to immune escape. In parallel, the influence of the lung and gut microbiome on shaping immunotherapy responses is discussed, with emphasis on microbial dysbiosis, immunosuppressive metabolite production, and TME remodeling. Therapeutic strategies to overcome resistance are also discussed, including combination approaches involving chemotherapy, radiotherapy, and antiangiogenic agents, as well as epigenetic modulators (HDAC and BET inhibitors). Moreover, the review explores bispecific antibodies, antibody-drug conjugates, and small-molecule agents that enhance T cell function or disrupt immunosuppressive signaling networks. By integrating insights from preclinical models and clinical trials, the review underscores the necessity of biomarker-guided patient stratification, combination immunotherapy approaches, and interventions that restore tumor immunogenicity. It concludes that a multipronged therapeutic strategy, one that addresses both immune evasion and TME-induced suppression, holds the greatest promise for improving response durability and advancing personalized immunotherapy for NSCLC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"250"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unleashing NK cells for cancer immunotherapy in lung cancer: biologic challenges and clinical advances.","authors":"Quinlan McLaughlin, Dorothy K Sojka, Kathleen Kennedy, Sytse J Piersma, Nan Sethakorn","doi":"10.1186/s13046-025-03503-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03503-7","url":null,"abstract":"<p><p>Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired immune tolerance, NK cell exhaustion, and the hypoxic state of the tumor microenvironment. Unleashing NK cell activity therefore has high potential to create a new class of immunotherapy that could combat both primary and acquired resistance to current checkpoint inhibitors. In this review we discuss mechanistic details of NK cell tumor killing, NK cell immunosuppression, and gaps in knowledge regarding highly complex microenvironment-specific effects on NK cell function. We also discuss the promise and limitations of emerging NK-cell based therapeutic strategies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"251"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.","authors":"Jiena Liu, Liuying Zhao, Meisi Yan, Shengye Jin, Lingmin Shang, Jianyu Wang, Qin Wang, Shilu Zhao, Zibo Shen, Tong Liu, Hao Wu, Da Pang","doi":"10.1186/s13046-025-03512-6","DOIUrl":"https://doi.org/10.1186/s13046-025-03512-6","url":null,"abstract":"<p><p>Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"252"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}