Cell Death and Differentiation最新文献

{"title":"ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression","authors":"Martina Antoniolli, Maria Solovey, Johannes Adrian Hildebrand, Tabea Freyholdt, Carolin Dorothea Strobl, Deepak Bararia, William David Keay, Louisa Adolph, Michael Heide, Verena Passerini, Lis Winter, Lucas Wange, Wolfgang Enard, Susanne Thieme, Helmut Blum, Martina Rudelius, Julia Mergner, Christina Ludwig, Sebastian Bultmann, Marc Schmidt-Supprian, Heinrich Leonhardt, Marion Subklewe, Michael von Bergwelt-Baildon, Maria Colomé-Tatché, Oliver Weigert","doi":"10.1038/s41418-025-01445-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01445-3","url":null,"abstract":"<p>The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::<i>BCL2</i> translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in <i>ARID1A</i>. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility (“openness”). However, the mechanism how <i>ARID1A</i> mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced-stage disease at initial diagnosis and found that <i>ARID1A</i> mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that <i>ARID1A</i> mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect <i>FAS</i> promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates <i>FAS</i> expression, and ARID1A loss leads to reduced <i>RUNX3</i> promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis, and significantly diminished CAR T cell killing in functional experiments. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including CAR T cells.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"84 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival","authors":"Fatima Domenica Elisa De Palma, Jonathan G. Pol, Vincent Carbonnier, Sarah Adriana Scuderi, Deborah Mannino, Léa Montégut, Allan Sauvat, Maria Perez-Lanzon, Elisabet Uribe-Carretero, Mario Guarracino, Ilaria Granata, Raffaele Calogero, Valentina Del Monaco, Donatella Montanaro, Gautier Stoll, Gerardo Botti, Massimiliano D’Aiuto, Alfonso Baldi, Valeria D’Argenio, Roderic Guigó, René Rezsohazy, Guido Kroemer, Maria Chiara Maiuri, Francesco Salvatore","doi":"10.1038/s41418-024-01430-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01430-2","url":null,"abstract":"<p>Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the <i>Homeobox A2</i> (<i>HOXA2</i>) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of <i>HOXA2</i> in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of <i>HOXA2</i> was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of <i>HOXA2</i> and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of <i>HOXA2</i> in human BC tissues. Low <i>HOXA2</i> expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of <i>HOXA2</i> expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic <i>HOXA2</i> overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored <i>HOXA2</i> expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of <i>HOXA2</i> leaded to a concomitantly decreased expression of <i>PPARγ</i> and its target <i>CIDEC</i>, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies <i>HOXA2</i> as a novel prognosis-relevant tumor suppressor in the mammary gland.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice","authors":"Leiming Jin, Weiwei Zhu, Xiang Hu, Lin Ye, Shuaijie Lou, Qianhui Zhang, Minxiu Wang, Bozhi Ye, Julian Min, Yi Wang, Lijiang Huang, Wu Luo, Guang Liang","doi":"10.1038/s41418-025-01444-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01444-4","url":null,"abstract":"<p>Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. <i>Usp25</i> deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25’s protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα’s lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of <i>Usp25</i> induction are nullified in <i>Ppara</i>-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"23 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation","authors":"Xiaolu Wang, Qianqian Wang, Hong Wang, Guodi Cai, Yana An, Peiqing Liu, Huihao Zhou, Hong-Wu Chen, Shufeng Ji, Jiantao Ye, Junjian Wang","doi":"10.1038/s41418-025-01443-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01443-5","url":null,"abstract":"<p>Clinical treatment options for triple-negative breast cancer (TNBC) are currently limited to chemotherapy because of a lack of effective therapeutic targets. Recent evidence suggests that long noncoding RNAs (lncRNAs) encode bioactive peptides or proteins, thereby playing noncanonical yet significant roles in regulating cellular processes. However, the potential of lncRNA-translated products in cancer progression remains largely unknown. In this study, we identified a previously undocumented small protein encoded by the lncRNA <i>LINC02870</i>. This protein is localized at the endoplasmic reticulum (ER) and participates in ER stress, thus, we named it the endoplasmic reticulum stress protein (ERSP). ERSP was highly expressed in TNBC tissues, and elevated <i>LINC02870</i> content was correlated with poor prognosis in TNBC patients. Loss of ERSP inhibited TNBC growth and metastasis both in vitro and in vivo. The pro-oncogenic effects of ERSP could be attributed to its selective activation of the IRE1α/XBP1s branch. ERSP enhances the unfolded protein response (UPR) by interacting with XBP1s, facilitating the nuclear accumulation of XBP1s, thereby promoting the expression of ER stress-related genes. These findings highlight the regulatory role of the lncRNA-encoded protein ERSP in ER stress and suggest that it is a potential therapeutic target for TNBC.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"49 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of regulated cell death during plant infection by the rice blast fungus Magnaporthe oryzae","authors":"Matthew R. Wengler, Nicholas J. Talbot","doi":"10.1038/s41418-024-01442-y","DOIUrl":"https://doi.org/10.1038/s41418-024-01442-y","url":null,"abstract":"<p>Fungi are the most important group of plant pathogens, responsible for many of the world’s most devastating crop diseases. One of the reasons they are such successful pathogens is because several fungi have evolved the capacity to breach the tough outer cuticle of plants using specialized infection structures called appressoria. This is exemplified by the filamentous ascomycete fungus <i>Magnaporthe oryzae</i>, causal agent of rice blast, one of the most serious diseases affecting rice cultivation globally. <i>M. oryzae</i> develops a pressurized dome-shaped appressorium that uses mechanical force to rupture the rice leaf cuticle. Appressoria form in response to the hydrophobic leaf surface, which requires the Pmk1 MAP kinase signalling pathway, coupled to a series of cell-cycle checkpoints that are necessary for regulated cell death of the fungal conidium and development of a functionally competent appressorium. Conidial cell death requires autophagy, which occurs within each cell of the spore, and is regulated by components of the cargo-independent autophagy pathway. This results in trafficking of the contents of all three cells to the incipient appressorium, which develops enormous turgor of up to 8.0 MPa, due to glycerol accumulation, and differentiates a thickened, melanin-lined cell wall. The appressorium then re-polarizes, re-orienting the actin and microtubule cytoskeleton to enable development of a penetration peg in a perpendicular orientation, that ruptures the leaf surface using mechanical force. Re-polarization requires septin GTPases which form a ring structure at the base of the appressorium, which delineates the point of plant infection, and acts as a scaffold for actin re-localization, enhances cortical rigidity, and forms a lateral diffusion barrier to focus polarity determinants that regulate penetration peg formation. Here we review the mechanism of regulated cell death in <i>M. oryzae</i>, which requires autophagy but may also involve ferroptosis. We critically evaluate the role of regulated cell death in appressorium morphogenesis and examine how it is initiated and regulated, both temporally and spatially, during plant infection. We then use this synopsis to present a testable model for control of regulated cell death during appressorium-dependent plant infection by the blast fungus.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tenascin-C promotes bone regeneration via inflammatory macrophages","authors":"Qian Ren, Wenhui Xing, Bo Jiang, Heng Feng, Xuye Hu, Jinlong Suo, Lijun Wang, Weiguo Zou","doi":"10.1038/s41418-024-01429-9","DOIUrl":"https://doi.org/10.1038/s41418-024-01429-9","url":null,"abstract":"<p>During the early stage of tissue injury, macrophages play important roles in the activation of stem cells for further regeneration. However, the regulation of macrophages during bone regeneration remains unclear. Here, the extracellular matrix (ECM) tenascin-C (TNC) is found to express in the periosteum and recruit inflammatory macrophages. TNC-deficiency in the periosteum delays bone repair. Transplantation of macrophages derived from injured periosteum is able to rescue the decreased skeletal stem cells and impaired bone regeneration caused by TNC deficiency. The cell communication analysis identifies ITGA7 as a TNC receptor contributing to the recruitment of inflammatory macrophages. TNC expression declines in aged mice and the exogenous delivery of TNC significantly promotes bone regeneration after aging through the recruitment of macrophages. Taken together, this study reveals the regulation of macrophage recruitment and its function in the activation of skeletal stem cells after bone injury, providing a strategy to accelerate bone regeneration by TNC delivery.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inactivation of GSK3β by Ser389 phosphorylation prevents thymocyte necroptosis and impacts Tcr repertoire diversity","authors":"Felipe Valença-Pereira, Ryan M. Sheridan, Kent A. Riemondy, Tina Thornton, Qian Fang, Brad Barret, Gabriela Paludo, Claudia Thompson, Patrick Collins, Mario Santiago, Eugene Oltz, Mercedes Rincon","doi":"10.1038/s41418-024-01441-z","DOIUrl":"https://doi.org/10.1038/s41418-024-01441-z","url":null,"abstract":"<p>The assembly of <i>Tcrb</i> and <i>Tcra</i> genes require double negative (DN) thymocytes to undergo multiple rounds of programmed DNA double-strand breaks (DSBs), followed by their efficient repair. However, mechanisms governing cell cycle checkpoints and specific survival pathways during the repair process remain unclear. Here, we report high-resolution scRNA-seq analyses of individually sorted mouse DN3 and DN4 thymocytes, which reveals a G2M cell cycle checkpoint, in addition to the known G1 checkpoint, during <i>Tcrb</i> and <i>Tcra</i> recombination. We also show that inactivation of GSK3β by phosphorylation on Ser³⁸⁹ is essential for DN3/DN4 thymocytes to survive while being stalled at the G1 and G2/M checkpoints. GSK3β promotes death by necroptosis, but not by apoptosis, of DN3/DN4 thymocytes during V(D)J recombination. Failure to inactivate GSK3β in DN3 thymocytes alters the <i>Tcrb</i> gene repertoire primarily through <i>Trbv</i> segment utilization. In addition, preferential recombination of proximal V segments in <i>Tcra</i> depends on GSK3β inactivation. Our study identifies a unique thymocyte survival pathway, enabling them to undergo cell cycle checkpoints for DNA repair during V(D)J recombination of <i>Tcrb</i> and <i>Tcra</i> genes. Thymocyte survival during cell cycle checkpoints for V(D)J recombination DNA repair determines TCRα/β repertoire.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies","authors":"Julie A. MacDonald, Gary A. Bradshaw, Fleur Jochems, René Bernards, Anthony Letai","doi":"10.1038/s41418-024-01431-1","DOIUrl":"https://doi.org/10.1038/s41418-024-01431-1","url":null,"abstract":"<p>Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found little univariate predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT-263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT-263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT-263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the senolytics ABT-263 or the combination of dasatinib and quercetin (D + Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-XL was significantly correlated to senescent cell killing by both ABT-263 and D + Q, despite no significant changes in the gene or protein expression of BCL-XL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"125 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy","authors":"Peng Wang, Jiannan Qiu, Yuan Fang, Songmao Li, Kua Liu, Yin Cao, Guang Zhang, Zhongxia Wang, Xiaosong Gu, Junhua Wu, Chunping Jiang","doi":"10.1038/s41418-024-01437-9","DOIUrl":"https://doi.org/10.1038/s41418-024-01437-9","url":null,"abstract":"<p>The importance of SUMOylation in tumorigenesis has received increasing attention, and research on therapeutic agents targeting this pathway has progressed. However, the potential function of SUMOylation during hepatocellular carcinoma (HCC) progression and the underlying molecular mechanisms remain unclear. Here, we identified that SUMO-Specific Peptidase 3 (SENP3) was upregulated in HCC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP3 promotes the malignant phenotype of HCC cells. Mechanistically, SENP3 deSUMOylates RACK1 and subsequently increases its stability and interaction with PKCβII, thereby promoting eIF4E phosphorylation and translation of oncogenes, including Bcl2, Snail and Cyclin D1. Additionally, tumor-intrinsic SENP3 promotes the infiltration of tumor-associated macrophages (TAMs) while reducing cytotoxic T cells to facilitate immune evasion. Mechanistically, SENP3 promotes translation of CCL20 via the RACK1 /eIF4E axis. Liver-specific knockdown of SENP3 significantly inhibits liver tumorigenesis in a chemically induced HCC model. SENP3 inhibition enhances the therapeutic efficacy of PD-1 blockade in an HCC mouse model. Collectively, SENP3 plays cell-intrinsic and cell-extrinsic roles in HCC progression and immune evasion by modulating oncogene and cytokine translation. Targeting SENP3 is a novel therapeutic target for boosting HCC responsiveness to immunotherapy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABCF1-K430-Lactylation promotes HCC malignant progression via transcriptional activation of HIF1 signaling pathway","authors":"Han Hong, Hexu Han, Lei Wang, Wen Cao, Minjie Hu, Jindong Li, Jiawei Wang, Yijin Yang, XiaoYong Xu, Gaochao Li, Zixiang Zhang, Changhe Zhang, Minhui Xu, Honggang Wang, Qiang Wang, Yin Yuan","doi":"10.1038/s41418-024-01436-w","DOIUrl":"https://doi.org/10.1038/s41418-024-01436-w","url":null,"abstract":"<p>Lysine lactylation plays critical roles in various diseases, including cancer. Our previous study showed that lactylation of non-histone ABCF1 may be involved in hepatocellular carcinoma (HCC) progression. In this study, we evaluated the prognostic value of ABCF1-K430la in HCC using immunohistochemical staining and performed amino acid point mutations, multi-omics crossover, and biochemical experiments to investigate its biological role and underlying mechanism. Additionally, we performed molecular docking on lactylation sites. ABCF1-K430la was highly expressed in HCC tissues and correlated with poor patient prognosis. Functionally, ABCF1-K430la promoted HCC growth and lung metastasis. Mechanistically, upon lactylation, E2 ubiquitin ligase activity of ABCF1 remained unaffected, and ABCF1 entered the nucleus, bound to the KDM3A promoter to upregulate its expression, and activated the KDM3A-H3K9me2-HIF1A axis, challenging the notion that ABCF1 functions exclusively in cytoplasmic protein translation. Notably, we discovered the existence of a lactate-ABCF1(430Kla)-HIF1A-lactate in HCC. A small-molecule drug screen targeting ABCF1-K430la revealed that tubuloside A inhibits ABCF1-K430la and suppresses HCC development. These findings demonstrate that elevated ABCF1-K430la expression promotes HCC development, suggesting it as a potential prognostic biomarker and therapeutic target for HCC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}