Molecular Cancer最新文献

{"title":"Deciphering a profiling based on multiple post-translational modifications functionally associated regulatory patterns and therapeutic opportunities in human hepatocellular carcinoma","authors":"Yuanxiang Lao, Yirong Jin, Songfeng Wu, Ting Fang, Qiang Wang, Longqin Sun, Beicheng Sun","doi":"10.1186/s12943-024-02199-1","DOIUrl":"https://doi.org/10.1186/s12943-024-02199-1","url":null,"abstract":"Posttranslational modifications (PTMs) play critical roles in hepatocellular carcinoma (HCC). However, the locations of PTM-modified sites across protein secondary structures and regulatory patterns in HCC remain largely uncharacterized. Total proteome and nine PTMs (phosphorylation, acetylation, crotonylation, ubiquitination, lactylation, N-glycosylation, succinylation, malonylation, and β-hydroxybutyrylation) in tumor sections and paired normal adjacent tissues derived from 18 HCC patients were systematically profiled by 4D-Label free proteomics analysis combined with PTM-based peptide enrichment. We detected robust preferences in locations of intrinsically disordered protein regions (IDRs) with phosphorylated sites and other site biases to locate in folded regions. Integrative analyses revealed that phosphorylated and multiple acylated-modified sites are enriched in proteins containing RRM1 domain, and RNA splicing is the key feature of this subset of proteins, as indicated by phosphorylation and acylation of splicing factor NCL at multiple residues. We confirmed that NCL-S67, K398, and K646 cooperate to regulate RNA processing. Together, this proteome profiling represents a comprehensive study detailing regulatory patterns based on multiple PTMs of HCC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"41 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer","authors":"Xing Zhou, Jiashu Han, Anning Zuo, Yuhao Ba, Shutong Liu, Hui Xu, Yuyuan Zhang, Siyuan Weng, Zhaokai Zhou, Long Liu, Peng Luo, Quan Cheng, Chuhan Zhang, Yukang Chen, Dan Shan, Benyu Liu, Shuaixi Yang, Xinwei Han, Jinhai Deng, Zaoqu Liu","doi":"10.1186/s12943-024-02180-y","DOIUrl":"https://doi.org/10.1186/s12943-024-02180-y","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) exert multiple tumor-promoting functions and are key contributors to drug resistance. The mechanisms by which specific subsets of CAFs facilitate oxaliplatin resistance in colorectal cancer (CRC) have not been fully explored. This study found that THBS2 is positively associated with CAF activation, epithelial-mesenchymal transition (EMT), and chemoresistance at the pan-cancer level. Together with single-cell RNA sequencing and spatial transcriptomics analyses, we identified THBS2 specifically derived from subsets of CAFs, termed THBS2 + CAFs, which could promote oxaliplatin resistance by interacting with malignant cells via the collagen pathway in CRC. Mechanistically, COL8A1 specifically secreted from THBS2 + CAFs directly interacts with the ITGB1 receptor on resistant malignant cells, activating the PI3K-AKT signaling pathway and promoting EMT, ultimately leading to oxaliplatin resistance in CRC. Moreover, elevated COL8A1 promotes EMT and contributes to CRC oxaliplatin resistance, which can be mitigated by ITGB1 knockdown or AKT inhibitor. Collectively, these results highlight the crucial role of THBS2 + CAFs in promoting oxaliplatin resistance of CRC by activating EMT and provide a rationale for a novel strategy to overcome oxaliplatin resistance in CRC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"263 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in A-to-I RNA editing in cancer","authors":"Yi Zhang, Lvyuan Li, Juana Jessica Mendoza, Dan Wang, Qijia Yan, Lei Shi, Zhaojian Gong, Zhaoyang Zeng, Pan Chen, Wei Xiong","doi":"10.1186/s12943-024-02194-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02194-6","url":null,"abstract":"RNA modifications are widespread throughout the mammalian transcriptome and play pivotal roles in regulating various cellular processes. These modifications are strongly linked to the development of many cancers. One of the most prevalent forms of RNA modifications in humans is adenosine-to-inosine (A-to-I) editing, catalyzed by the enzyme adenosine deaminase acting on RNA (ADAR) in double-stranded RNA (dsRNA). With advancements in RNA sequencing technologies, the role of A-to-I modification in cancer has garnered increasing attention. Research indicates that the levels and specific sites of A-to-I editing are significantly altered in many malignant tumors, correlating closely with tumor progression. This editing occurs in both coding and noncoding regions of RNA, influencing signaling pathways involved in cancer development. These modifications can either promote or suppress cancer progression through several mechanisms, including inducing non-synonymous amino acid mutations, altering the immunogenicity of dsRNAs, modulating mRNA interactions with microRNAs (miRNAs), and affecting the splicing of circular RNAs (circRNAs) as well as the function of long non-coding RNAs (lncRNAs). A comprehensive understanding of A-to-I RNA editing is crucial for advancing the diagnosis, treatment, and prognosis of human cancers. This review explores the regulatory mechanisms of A-to-I editing in cancers and examines their potential clinical applications. It also summarizes current research, identifies future directions, and highlights potential therapeutic implications.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"32 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutation of lysine-specific demethylase 5 is associated with enhanced tumor immunity and favorable outcomes in pan-cancer immune checkpoint blockade","authors":"Xiaofeng Li, Zhishan Zhang, Yingying Li, Lijin Chen, Yan Huang, Lijuan Su, Wenjun Xu, Yanni Hong, Jianjiao Li, Mujin Chen, Hongkui Yang, Hong Zhao, Bin Zhao","doi":"10.1186/s12943-024-02197-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02197-3","url":null,"abstract":"The lysine-specific demethylase 5 (KDM5) family, a key post-translational modification of chromatin, can shape tumor immune microenvironment. Here, we performed an extensive clinical and bioinformatic analysis to explore the association between KDM5 mutation and tumor immunity and its impact on the outcomes in pan-cancer immunotherapy. In 2943 patients across 12 tumor types treated with immune checkpoint inhibitors, KDM5-mutant tumors were associated with favorable overall survival (hazard ratio, 0.72; 95% confidence interval, 0.59–0.87; P = 0.004) and objective response rate (41.7% vs. 26.8%; P = 0.001). Further multi-omics analysis revealed KDM5 mutation was related to boosted tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses. In summary, KDM5 mutation indicates enhanced tumor immunity and favorable outcomes in pan-cancer immune checkpoint blockade. These results have implication for treatment decision-making and developing immunotherapy for personalized care.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"63 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current trends in sensitizing immune checkpoint inhibitors for cancer treatment","authors":"Jing Wei, Wenke Li, Pengfei Zhang, Fukun Guo, Ming Liu","doi":"10.1186/s12943-024-02179-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02179-5","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune checkpoint blockade (ICB) remains a critical clinical challenge, characterized by variable response rates and non-durable benefits. However, growing research into the complex intrinsic and extrinsic characteristics of tumors has advanced our understanding of the mechanisms behind ICI resistance, potentially improving treatment outcomes. Additionally, robust predictive biomarkers are crucial for optimizing patient selection and maximizing the efficacy of ICBs. Recent studies have emphasized that multiple rational combination strategies can overcome immune checkpoint resistance and enhance susceptibility to ICIs. These findings not only deepen our understanding of tumor biology but also reveal the unique mechanisms of action of sensitizing agents, extending clinical benefits in cancer immunotherapy. In this review, we will explore the underlying biology of ICIs, discuss the significance of the tumor immune microenvironment (TIME) and clinical predictive biomarkers, analyze the current mechanisms of resistance, and outline alternative combination strategies to enhance the effectiveness of ICIs, including personalized strategies for sensitizing tumors to ICIs.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"299 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1","authors":"Xin Zang, Xiao‑Yu He, Cheng‑Mei Xiao, Qing Lin, Meng‑Yue Wang, Cheng‑Yan Liu, Ling‑Yi Kong, Zhong Chen, Yuan‑Zheng Xia","doi":"10.1186/s12943-024-02200-x","DOIUrl":"https://doi.org/10.1186/s12943-024-02200-x","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Mol Cancer 23, 207 (2024)</b></p><p><b>https://doi.org/10.1186/s12943-024-02124-6</b></p><br/><p>Following publication of the original article [1], the authors identified several inaccuracies, shown as follows:</p><ul>\u0000<li>\u0000<p>In Figure 2g, the B16-F10 linear-108aa overexpression group incorrectly utilized the loading control from B16-F10 circPIAS1 overexpression group shown in Figure 4a.</p>\u0000</li>\u0000<li>\u0000<p>In Figure 2h, the B16-F10 ASOs knockdown group incorrectly used the loading control from the same group shown in Figure 4a.</p>\u0000</li>\u0000<li>\u0000<p>Additionally, we recommend changing the vertical title in Figure 3-a (lower) to 'Relative circPIAS1 ORF levels' for improved accuracy.</p>\u0000</li>\u0000</ul><p>The incorrect and correct Figures 2 and 3 are given below.</p><p>Incorrect Figure 2:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figa_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"1002\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figa_HTML.png\" width=\"685\"/></picture></figure><p>Incorrect Figure 3:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figb_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure b\" aria-describedby=\"Figb\" height=\"859\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figb_HTML.png\" width=\"685\"/></picture></figure><p>Correct Figure 2:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figc_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure c\" aria-describedby=\"Figc\" height=\"1002\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figc_HTML.png\" width=\"685\"/></picture></figure><p>Correct Figure 3:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figd_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure d\" aria-describedby=\"Figd\" height=\"859\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-024-02200-x/MediaObjects/12943_2024_2200_Figd_HTML.png\" width=\"685\"/></picture></figure><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Zang X, He XY, Xiao CM, et al. Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1. Mol Cancer. 2024;23:207. https://doi.org/10.1186/s12943-0","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"89 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomedicines harnessing cGAS-STING pathway: sparking immune revitalization to transform ‘cold’ tumors into ‘hot’ tumors","authors":"Xiaohong Ying, Qiaohui Chen, Yongqi Yang, Ziyu Wu, Wan Zeng, Chenxi Miao, Qiong Huang, Kelong Ai","doi":"10.1186/s12943-024-02186-6","DOIUrl":"https://doi.org/10.1186/s12943-024-02186-6","url":null,"abstract":"cGAS-STING pathway stands at the forefront of innate immunity and plays a critical role in regulating adaptive immune responses, making it as a key orchestrator of anti-tumor immunity. Despite the great potential, clinical outcomes with cGAS-STING activators have been disappointing due to their unfavorable in vivo fate, signaling an urgent need for innovative solutions to bridge the gap in clinical translation. Recent advancements in nanotechnology have propelled cGAS-STING-targeting nanomedicines to the cutting-edge of cancer therapy, leveraging precise drug delivery systems and multifunctional platforms to achieve remarkable region-specific biodistribution and potent therapeutic efficacy. In this review, we provide an in-depth exploration of the molecular mechanisms that govern cGAS-STING signaling and its potential to dynamically modulate the anti-tumor immune cycle. We subsequently introduced several investigational cGAS-STING-dependent anti-tumor agents and summarized their clinical trial progress. Additionally, we provided a comprehensive review of the unique advantages of cGAS-STING-targeted nanomedicines, highlighting the transformative potential of nanotechnology in this field. Furthermore, we comprehensively reviewed and comparatively analyzed the latest breakthroughs cGAS-STING-targeting nanomedicine, focusing on strategies that induce cytosolic DNA generation via exogenous DNA delivery, chemotherapy, radiotherapy, or dynamic therapies, as well as the nanodelivery of STING agonists. Lastly, we discuss the future prospects and challenges in cGAS-STING-targeting nanomedicine development, offering new insights to bridge the gap between mechanistic research and drug development, thereby opening new pathways in cancer treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the mysteries of extrachromosomal circular DNA: from generation to clinical relevance in human cancers and health","authors":"Zilong Wang, Jiaying Yu, Wenli Zhu, Xiaoning Hong, Zhen Xu, Shuang Mao, Lei Huang, Peng Han, Chunxiao He, Changze Song, Xi Xiang","doi":"10.1186/s12943-024-02187-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02187-5","url":null,"abstract":"Extrachromosomal circular DNAs (eccDNAs) are a type of circular DNAs originating from but independent of chromosomal DNAs. Nowadays, with the rapid development of sequencing and bioinformatics, the accuracy of eccDNAs detection has significantly improved. This advancement has consequently enhanced the feasibility of exploring the biological characteristics and functions of eccDNAs. This review elucidates the potential mechanisms of eccDNA generation, the existing methods for their detection and analysis, and their basic features. Furthermore, it focuses on the biological functions of eccDNAs in regulating gene expression under both physiological and pathological conditions. Additionally, the review summarizes the clinical implications of eccDNAs in human cancers and health.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-based classification of anticancer drugs reveals nucleolar condensation as a predictor of immunogenicity","authors":"Giulia Cerrato, Peng Liu, Liwei Zhao, Adriana Petrazzuolo, Juliette Humeau, Sophie Theresa Schmid, Mahmoud Abdellatif, Allan Sauvat, Guido Kroemer","doi":"10.1186/s12943-024-02189-3","DOIUrl":"https://doi.org/10.1186/s12943-024-02189-3","url":null,"abstract":"Immunogenic cell death (ICD) inducers are often identified in phenotypic screening campaigns by the release or surface exposure of various danger-associated molecular patterns (DAMPs) from malignant cells. This study aimed to streamline the identification of ICD inducers by leveraging cellular morphological correlates of ICD, specifically the condensation of nucleoli (CON). We applied artificial intelligence (AI)-based imaging analyses to Cell Paint-stained cells exposed to drug libraries, identifying CON as a marker for ICD. CON was characterized using SYTO 14 fluorescent staining and holotomographic microscopy, and visualized by AI-deconvoluted transmitted light microscopy. A neural network-based quantitative structure-activity relationship (QSAR) model was trained to link molecular descriptors of compounds to the CON phenotype, and the classifier was validated using an independent dataset from the NCI-curated mechanistic collection of anticancer agents. CON strongly correlated with the inhibition of DNA-to-RNA transcription. Cytotoxic drugs that inhibit RNA synthesis without causing DNA damage were as effective as conventional cytotoxicants in inducing ICD, as demonstrated by DAMPs release/exposure and vaccination efficacy in mice. The QSAR classifier successfully predicted drugs with a high likelihood of inducing CON. We developed AI-based algorithms for predicting CON-inducing drugs based on molecular descriptors and their validation using automated micrographs analysis, offering a new approach for screening ICD inducers with minimized adverse effects in cancer therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis","authors":"Yaqi Mo, Yamei Han, Yang Chen, Chunling Fu, Qing Li, Zhuang Liu, Mingming Xiao, Bo Xu","doi":"10.1186/s12943-024-02195-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02195-5","url":null,"abstract":"Protein palmitoylation is a reversible fatty acyl modification that undertakes important functions in multiple physiological processes. Dysregulated palmitoylations are frequently associated with the formation of cancer. How palmitoyltransferases for S-palmitoylation are involved in the occurrence and development of hepatocellular carcinoma (HCC) is largely unknown. Chemical carcinogen diethylnitrosamine (DEN)-induced and DEN combined CCl4 HCC models were used in the zinc finger DHHC-type palmitoyltransferase 20 (ZDHHC20) knockout mice to investigate the role of ZDHHC20 in HCC tumourigenesis. Palmitoylation liquid chromatography-mass spectrometry analysis, acyl-biotin exchange assay, co-immunoprecipitation, ubiquitination assays, protein half-life assays and immunofluorescence microscopy were conducted to explore the downstream regulators and corresponding mechanisms of ZDHHC20 in HCC. Knocking out of ZDHHC20 significantly reduced hepatocarcinogenesis induced by chemical agents in the two HCC mouse models in vivo. 97 proteins with 123 cysteine sites were found to be palmitoylated in a ZDHHC20-dependent manner. Among these, fatty acid synthase (FASN) was palmitoylated at cysteines 1471 and 1881 by ZDHHC20. The genetic knockout or pharmacological inhibition of ZDHHC20, as well as the mutation of the critical cysteine sites of FASN (C1471S/C1881S) accelerated the degradation of FASN. Furthermore, ZDHHC20-mediated FASN palmitoylation competed against the ubiquitin-proteasome pathway via the E3 ubiquitin ligase complex SNX8-TRIM28. Our findings demonstrate the critical role of ZDHHC20 in promoting hepatocarcinogenesis, and a mechanism underlying a mutual restricting mode for protein palmitoylation and ubiquitination modifications.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}