C1Q+ TPP1+巨噬细胞通过setd8驱动的p53甲基化促进结肠癌进展

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Veronica Veschi, Francesco Verona, Sebastiano Di Bella, Alice Turdo, Miriam Gaggianesi, Simone Di Franco, Laura Rosa Mangiapane, Chiara Modica, Melania Lo Iacono, Paola Bianca, Ornella Roberta Brancato, Caterina D’Accardo, Gaetana Porcelli, Vincenzo Luca Lentini, Isabella Sperduti, Elisabetta Sciacca, Peter Fitzgerald, David Lopez-Perez, Pierre Martine, Kate Brown, Giuseppe Giannini, Ettore Appella, Giorgio Stassi, Matilde Todaro
{"title":"C1Q+ TPP1+巨噬细胞通过setd8驱动的p53甲基化促进结肠癌进展","authors":"Veronica Veschi, Francesco Verona, Sebastiano Di Bella, Alice Turdo, Miriam Gaggianesi, Simone Di Franco, Laura Rosa Mangiapane, Chiara Modica, Melania Lo Iacono, Paola Bianca, Ornella Roberta Brancato, Caterina D’Accardo, Gaetana Porcelli, Vincenzo Luca Lentini, Isabella Sperduti, Elisabetta Sciacca, Peter Fitzgerald, David Lopez-Perez, Pierre Martine, Kate Brown, Giuseppe Giannini, Ettore Appella, Giorgio Stassi, Matilde Todaro","doi":"10.1186/s12943-025-02293-y","DOIUrl":null,"url":null,"abstract":"In many tumors, the tumor suppressor TP53 is not mutated, but functionally inactivated. However, mechanisms underlying p53 functional inactivation remain poorly understood. SETD8 is the sole enzyme known to mono-methylate p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. We analyzed SETD8 and p53K382me1 expression in clinical colorectal cancer (CRC) and inflammatory bowel disease (IBD) samples. Histopathological examinations, RNA sequencing, ChIP assay and preclinical in vivo CRC models, were used to assess the functional role of p53 inactivation in tumor cells and immune cell infiltration. By integrating bulk RNAseq and scRNAseq approaches in CRC patients, SETD8-mediated p53 regulation resulted the most significantly enriched pathway. p53K382me1 expression was confined to colorectal cancer stem cells (CR-CSCs) and C1Q+ TPP1+ tumor-associated macrophages (TAMs) in CRC patient tissues, with high levels predicting decreased survival probability. TAMs promote p53 functional inactivation in CR-CSCs through IL-6 and MCP-1 secretion and increased levels of CEBPD, which directly binds SETD8 promoter thus enhancing its transcription. The direct binding of C1Q present on macrophages and C1Q receptor (C1QR) present on cancer stem cells mediates the cross-talk between the two cell compartments. As monotherapy, SETD8 genetic and pharmacological (UNC0379) inhibition affects the tumor growth and metastasis formation in CRC mouse avatars, with enhanced effects observed when combined with IL-6 receptor targeting. These findings suggest that p53K382me1 may be an early step in tumor initiation, especially in inflammation-induced CRC, and could serve as a functional biomarker and therapeutic target in adjuvant setting for advanced CRCs. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"183 1","pages":""},"PeriodicalIF":27.7000,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"C1Q+ TPP1+ macrophages promote colon cancer progression through SETD8-driven p53 methylation\",\"authors\":\"Veronica Veschi, Francesco Verona, Sebastiano Di Bella, Alice Turdo, Miriam Gaggianesi, Simone Di Franco, Laura Rosa Mangiapane, Chiara Modica, Melania Lo Iacono, Paola Bianca, Ornella Roberta Brancato, Caterina D’Accardo, Gaetana Porcelli, Vincenzo Luca Lentini, Isabella Sperduti, Elisabetta Sciacca, Peter Fitzgerald, David Lopez-Perez, Pierre Martine, Kate Brown, Giuseppe Giannini, Ettore Appella, Giorgio Stassi, Matilde Todaro\",\"doi\":\"10.1186/s12943-025-02293-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"In many tumors, the tumor suppressor TP53 is not mutated, but functionally inactivated. However, mechanisms underlying p53 functional inactivation remain poorly understood. SETD8 is the sole enzyme known to mono-methylate p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. We analyzed SETD8 and p53K382me1 expression in clinical colorectal cancer (CRC) and inflammatory bowel disease (IBD) samples. Histopathological examinations, RNA sequencing, ChIP assay and preclinical in vivo CRC models, were used to assess the functional role of p53 inactivation in tumor cells and immune cell infiltration. By integrating bulk RNAseq and scRNAseq approaches in CRC patients, SETD8-mediated p53 regulation resulted the most significantly enriched pathway. p53K382me1 expression was confined to colorectal cancer stem cells (CR-CSCs) and C1Q+ TPP1+ tumor-associated macrophages (TAMs) in CRC patient tissues, with high levels predicting decreased survival probability. TAMs promote p53 functional inactivation in CR-CSCs through IL-6 and MCP-1 secretion and increased levels of CEBPD, which directly binds SETD8 promoter thus enhancing its transcription. The direct binding of C1Q present on macrophages and C1Q receptor (C1QR) present on cancer stem cells mediates the cross-talk between the two cell compartments. As monotherapy, SETD8 genetic and pharmacological (UNC0379) inhibition affects the tumor growth and metastasis formation in CRC mouse avatars, with enhanced effects observed when combined with IL-6 receptor targeting. These findings suggest that p53K382me1 may be an early step in tumor initiation, especially in inflammation-induced CRC, and could serve as a functional biomarker and therapeutic target in adjuvant setting for advanced CRCs. \",\"PeriodicalId\":19000,\"journal\":{\"name\":\"Molecular Cancer\",\"volume\":\"183 1\",\"pages\":\"\"},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2025-03-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12943-025-02293-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12943-025-02293-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

在许多肿瘤中,肿瘤抑制因子TP53不是突变,而是功能失活。然而,p53功能失活的机制仍然知之甚少。SETD8是已知的唯一能将p53单甲基化到赖氨酸382 (p53K382me1)上的酶,从而抑制其促凋亡和生长抑制功能。我们分析了SETD8和p53K382me1在临床结直肠癌(CRC)和炎症性肠病(IBD)样本中的表达。通过组织病理学检查、RNA测序、ChIP检测和临床前CRC体内模型来评估p53失活在肿瘤细胞和免疫细胞浸润中的功能作用。通过整合CRC患者的bulk RNAseq和scRNAseq方法,setd8介导的p53调控导致了最显著的富集途径。p53K382me1的表达仅限于结直肠癌患者组织中的结直肠癌干细胞(CR-CSCs)和C1Q+ TPP1+肿瘤相关巨噬细胞(tam),其高水平表达预示着生存率降低。tam通过IL-6、MCP-1分泌和CEBPD水平升高,促进CR-CSCs中p53功能失活,CEBPD直接结合SETD8启动子,增强其转录。巨噬细胞上存在的C1Q与癌症干细胞上存在的C1Q受体(C1QR)的直接结合介导了两个细胞间的串扰。作为单一疗法,SETD8基因和药理学(UNC0379)抑制可影响结直肠癌小鼠的肿瘤生长和转移形成,当与IL-6受体靶向联合使用时,效果增强。这些发现表明p53K382me1可能是肿瘤起始的早期步骤,特别是在炎症诱导的CRC中,并且可以作为晚期CRC辅助设置的功能性生物标志物和治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
C1Q+ TPP1+ macrophages promote colon cancer progression through SETD8-driven p53 methylation
In many tumors, the tumor suppressor TP53 is not mutated, but functionally inactivated. However, mechanisms underlying p53 functional inactivation remain poorly understood. SETD8 is the sole enzyme known to mono-methylate p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. We analyzed SETD8 and p53K382me1 expression in clinical colorectal cancer (CRC) and inflammatory bowel disease (IBD) samples. Histopathological examinations, RNA sequencing, ChIP assay and preclinical in vivo CRC models, were used to assess the functional role of p53 inactivation in tumor cells and immune cell infiltration. By integrating bulk RNAseq and scRNAseq approaches in CRC patients, SETD8-mediated p53 regulation resulted the most significantly enriched pathway. p53K382me1 expression was confined to colorectal cancer stem cells (CR-CSCs) and C1Q+ TPP1+ tumor-associated macrophages (TAMs) in CRC patient tissues, with high levels predicting decreased survival probability. TAMs promote p53 functional inactivation in CR-CSCs through IL-6 and MCP-1 secretion and increased levels of CEBPD, which directly binds SETD8 promoter thus enhancing its transcription. The direct binding of C1Q present on macrophages and C1Q receptor (C1QR) present on cancer stem cells mediates the cross-talk between the two cell compartments. As monotherapy, SETD8 genetic and pharmacological (UNC0379) inhibition affects the tumor growth and metastasis formation in CRC mouse avatars, with enhanced effects observed when combined with IL-6 receptor targeting. These findings suggest that p53K382me1 may be an early step in tumor initiation, especially in inflammation-induced CRC, and could serve as a functional biomarker and therapeutic target in adjuvant setting for advanced CRCs.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信