Cell Death & Disease最新文献_第2页

Humanized mouse models in MDS. MDS人源化小鼠模型。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-17 DOI: 10.1038/s41419-025-07861-0

Raluca Munteanu, Diana Gulei, Cristian Silviu Moldovan, Emanuele Azzoni, Laura Belver, Richard Feder, Simina Pirv, Anca Dana Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert Hasserjian, Ciprian Tomuleasa

{"title":"Humanized mouse models in MDS.","authors":"Raluca Munteanu, Diana Gulei, Cristian Silviu Moldovan, Emanuele Azzoni, Laura Belver, Richard Feder, Simina Pirv, Anca Dana Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert Hasserjian, Ciprian Tomuleasa","doi":"10.1038/s41419-025-07861-0","DOIUrl":"10.1038/s41419-025-07861-0","url":null,"abstract":"Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell disorders defined by ineffective hematopoiesis, multilineage dysplasia, and risk of progression to acute myeloid leukemia. Improvements have been made to identify recurrent genetic mutations and their functional roles, but translating this into preclinical models is still difficult. Traditional murine systems lack the human-specific cytokine support and microenvironmental support that is necessary to reproduce MDS pathophysiology. Humanized mouse models, particularly those incorporating human cytokines (e.g., MISTRG, NSG-SGM3, NOG-EXL), immunodeficient backgrounds, and co-transplantation strategies, have improved the engraftment and differentiation of human hematopoietic stem and progenitor cells. These models allow the study of clonal evolution, mutation-specific disease dynamics, and response to therapies in vivo. However, difficulties persist, such as limited long-term engraftment, incomplete immune reconstruction, and limited possibilities of modeling early-stage or low-risk MDS. This review presents an overview of current humanized and genetically engineered mouse models suitable for studying MDS, evaluating their capacity to replicate disease complexity, preserve clonal architecture, and support translational research. We highlight the need to develop new approaches to improve the actual methodologies and propose future directions for standardization and improved clinical relevance.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"531"},"PeriodicalIF":8.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heat shock factor 1 promotes proliferation and chemoresistance in diffuse large B-cell lymphoma by enhancing the cell cycle and DNA repair. 热休克因子1通过增强细胞周期和DNA修复促进弥漫性大b细胞淋巴瘤的增殖和化疗耐药。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-17 DOI: 10.1038/s41419-025-07843-2

Yu Fang, Liang Cheng, Ming Huang, Yi Cao, Qihua Zou, Jun Cai, Yuchen Zhang, Yi Xia, Huiqiang Huang, Xu Chen, Qingqing Cai

{"title":"Heat shock factor 1 promotes proliferation and chemoresistance in diffuse large B-cell lymphoma by enhancing the cell cycle and DNA repair.","authors":"Yu Fang, Liang Cheng, Ming Huang, Yi Cao, Qihua Zou, Jun Cai, Yuchen Zhang, Yi Xia, Huiqiang Huang, Xu Chen, Qingqing Cai","doi":"10.1038/s41419-025-07843-2","DOIUrl":"10.1038/s41419-025-07843-2","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is commonly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but up to 40% of patients have refractory or relapsing disease and show unsatisfactory responses to salvage treatment. Heat shock factor 1 (HSF1) regulates the transcription of a group of oncogenes, promoting chemoresistance and representing a promising therapeutic target. However, the role and mechanism of HSF1 in DLBCL remain unknown. In this study, we discovered that the overexpression of HSF1 was correlated with unfavorable treatment response and poor prognosis in patients with DLBCL. Inhibition of HSF1 via shRNA or DTHIB, a pharmacological inhibitor of HSF1, inhibited cell proliferation and increased chemosensitivity to vincristine and doxorubicin both in vitro and in vivo. Mechanistically, we revealed that genes related to the cell cycle, DNA repair, and p53 signalling pathways, including CCNB1, CCNE2, E2F2, and XRCC2, were directly regulated by HSF1 in a protein arginine methyltransferase 5 (PRMT5) -dependent manner. These findings demonstrated that the significant transcriptional regulator HSF1 promoted cell proliferation and chemoresistance in DLBCL. Targeting HSF1 may serve as a promising therapeutic strategy that enhances the antitumor effects of chemotherapy in DLBCL.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"533"},"PeriodicalIF":8.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

12th International Multi Thematic Scientific Biomedical Congress (IMBMC), Nicosia, Cyprus, 2024. 第12届国际多主题科学生物医学大会（IMBMC），尼科西亚，塞浦路斯，2024。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-16 DOI: 10.1038/s41419-025-07865-w

Giannis Socratous, Maria Elia, Panayiota Christodoulou, Theodora-Christina Kyriakou, Christina Kousparou, Charalambos Michaeloudes, Petros Agathaggelou, Anastasis Stephanou, Ioannis Patrikios

引用次数: 0

Modeling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype. 模拟结直肠癌的奥沙利铂耐药揭示了基于serpine1的基因标记（resistance -m）和促转移性CMS4亚型的治疗策略。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-16 DOI: 10.1038/s41419-025-07855-y

Stephen Qi Rong Wong, Mohua Das, Kenzom Tenzin, Niranjan Shirgaonkar, Huiwen Chua, Lin Xuan Chee, Ahpa Sae Yeoh, Astley Aruna Murugiah, Wei Yong Chua, Madelaine Skolastika Theardy, Ethan Jadon Subel, Matan Thangavelu Thangavelu, Jane Vin Chan, Choon Kong Yap, Iain Bee Huat Tan, Petros Tsantoulis, Sabine Tejpar, Jia Min Loo, Ramanuj DasGupta

{"title":"Modeling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype.","authors":"Stephen Qi Rong Wong, Mohua Das, Kenzom Tenzin, Niranjan Shirgaonkar, Huiwen Chua, Lin Xuan Chee, Ahpa Sae Yeoh, Astley Aruna Murugiah, Wei Yong Chua, Madelaine Skolastika Theardy, Ethan Jadon Subel, Matan Thangavelu Thangavelu, Jane Vin Chan, Choon Kong Yap, Iain Bee Huat Tan, Petros Tsantoulis, Sabine Tejpar, Jia Min Loo, Ramanuj DasGupta","doi":"10.1038/s41419-025-07855-y","DOIUrl":"10.1038/s41419-025-07855-y","url":null,"abstract":"Drug resistance and distant metastases are leading causes of mortality in colorectal cancer (CRC), yet the molecular mechanisms linking these processes remain elusive. In this study, we demonstrate that acquired resistance to oxaliplatin, a first-line chemotherapeutic in CRC, enhances metastatic potential through transcriptional reprogramming. Using a clinically relevant dosing regimen, we generated oxaliplatin-resistant CRC cells that displayed increased metastatic potential. Integrated transcriptomic and phenotypic analyses revealed that dysregulated cholesterol biogenesis amplifies TGF-β signaling, which in turn drives expression of SERPINE1, which serves as a key effector of both oxaliplatin resistance and metastasis. Furthermore, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that robustly predicts overall and relapse-free survival across distinct patient cohorts. Notably, RESIST-M stratifies a high-risk subtype of CMS4/iCMS3-fibrotic patients that display the poorest prognosis, underscoring its clinical relevance. Targeting of SERPINE1 or cholesterol biosynthesis re-sensitized resistant, pro-metastatic cells to oxaliplatin in mouse xenograft models. Altogether, this study uncovers a mechanistic link between metabolic rewiring and transcriptional plasticity underlying therapy-induced metastasis in primary CRC. Additionally, it also reveals actionable vulnerabilities that offer both prognostic value and therapeutic potential.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"529"},"PeriodicalIF":8.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Simvastatin suppresses spinal cord metastasis of medulloblastoma at clinically significant doses. 辛伐他汀在临床显著剂量下抑制髓母细胞瘤脊髓转移。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07829-0

Charley Comer, Kian Cotton, Christopher Edwards, Xiaoyang Dai, Sara Badodi, Roberto Buccafusca, Chris Bennett, Andrew Peet, Alice Williams, David Michod, Elena Bochukova, Maria Victoria Niklison-Chirou

{"title":"Simvastatin suppresses spinal cord metastasis of medulloblastoma at clinically significant doses.","authors":"Charley Comer, Kian Cotton, Christopher Edwards, Xiaoyang Dai, Sara Badodi, Roberto Buccafusca, Chris Bennett, Andrew Peet, Alice Williams, David Michod, Elena Bochukova, Maria Victoria Niklison-Chirou","doi":"10.1038/s41419-025-07829-0","DOIUrl":"10.1038/s41419-025-07829-0","url":null,"abstract":"Medulloblastomas (MBs) are aggressive brain cancers and represent the most common primary malignant tumour in children. Current treatment protocols involve an intensive regimen of surgery, radiation therapy and chemotherapy, guided by histopathology and risk stratification. Unfortunately, disease relapse proves fatal in 30% of cases, and treatment efficacy is compromised as MB cells develop resistance. Therefore, there is a critical need for more effective and tolerable therapies, especially for the treatment of aggressive MBs associated with a poor prognosis. Lipid metabolism reprogramming, characterized by increased cholesterol synthesis, lipid uptake and the activation of de novo lipogenesis, is a newly identified hallmark of cancers. Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signalling events governing the hallmarks of cancer. Our research demonstrates there is an overexpression of cholesterol metabolism in group 3 (G3), and group 4 (G4) MB subgroups compared to Sonic Hedgehog (SHH)-MB subgroup. In these tumours, cholesterol metabolism supports cell migration through the Rho-GTPase signalling pathway. Notably, we observed that shifting the culture conditions from 2D to 3D significantly upregulates lipid metabolism. Furthermore, spheroids derived from G3/G4-MBs and SHH-MBs show similar sensitivity to low doses of simvastatin. We validated these findings in a xenograft mouse model, where treatment with low doses of simvastatin led to increased survival time and remarkably, also reduced the metastatic spread of MB cells to the spinal cord. These results suggest that simvastatin holds potential as an adjuvant treatment for patients with medulloblastoma.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"527"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis. 地西他滨联合放疗通过TFAP2C-OTUD1-SLC25A11轴增强鼻咽癌放射敏感性

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07858-9

Haixia Zhang, Siyang Liu, Dan Wang, Yaqi Liao, Shizhen Li, Jing He, Jie Shen, Lu Yan, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen

{"title":"Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis.","authors":"Haixia Zhang, Siyang Liu, Dan Wang, Yaqi Liao, Shizhen Li, Jing He, Jie Shen, Lu Yan, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen","doi":"10.1038/s41419-025-07858-9","DOIUrl":"10.1038/s41419-025-07858-9","url":null,"abstract":"Nasopharyngeal carcinoma (NPC) is a common malignancy in certain geographic regions, with radiotherapy serving as the primary treatment. Recent research shows that epigenetics and deubiquitinases (DUBs) are crucial in NPC progression and treatment response. However, the emergence of radioresistance in NPC cells presents a significant challenge, often resulting in treatment failure. This study focuses on understanding the role of OTUD1 and methylation in NPC radiosensitivity and their mechanisms. In this study, OTUD1 and TFAP2C expression were significantly reduced in radioresistant NPC cell lines, likely due to the high methylation of TFAP2C. OTUD1 is significantly downregulated in radioresistant NPC, and its low expression is associated with enhanced radioresistance both in vitro and in vivo. Mechanistically, OTUD1 enhances NPC radiosensitivity by deubiquitinating and stabilizing SLC25A11, leading to increased Reactive oxygen species (ROS) and apoptosis. Clinically, low OTUD1 and SLC25A11 expression is associated with poor radiotherapy response and survival outcomes. Furthermore, we demonstrate that combining the methylation inhibitor Decitabine (DAC) with radiotherapy significantly improves treatment efficacy by overcoming radioresistance. These findings provide insights into NPC radioresistance and suggest that using DAC in combination with radiotherapy to target the TFAP2C-OTUD1-SLC25A11 axis could be a promising strategy to overcome radioresistance.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"525"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe. 靶向递送PKMYT1抑制剂RP-6306通过有丝分裂突变介导胰腺癌PANoptosis。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07835-2

Jingyun Chen, Jianghao Ren, Chaolei Zhang, Yang Lv, Jingbin Zhou, Weiliang Jiang, Chaojie Huang, Liping Cao

{"title":"Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe.","authors":"Jingyun Chen, Jianghao Ren, Chaolei Zhang, Yang Lv, Jingbin Zhou, Weiliang Jiang, Chaojie Huang, Liping Cao","doi":"10.1038/s41419-025-07835-2","DOIUrl":"10.1038/s41419-025-07835-2","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor often diagnosed in advanced stages due to its subtle early symptoms, making surgical options nonviable and requiring systemic chemotherapy. Current treatments mainly utilize gemcitabine, which provides limited efficacy. PKMYT1, a serine/threonine protein kinase crucial for cell cycle regulation, is overexpressed in PDAC and correlates with poor prognosis. Treatment with the PKMYT1 inhibitor RP-6306 promotes rapid mitotic entry, resulting in DNA damage and mitotic catastrophe, thereby inducing PANoptosis. RP-6306 effectively inhibits PDAC growth in vitro and in vivo, and shows enhanced anti-tumor activity when combined with gemcitabine, also reducing metastasis. However, gemcitabine has notable systemic toxicity. To target cancer cells more specifically, we utilized vesicles derived from cell membranes (BxPC-3M) to deliver a combination of RP-6306 and gemcitabine (GEM + RP-6306@BxPC-3M). This formulation effectively targets homotypic tumor cells and significantly inhibits tumor growth both in vitro and in vivo. These findings highlight the role of RP-6306 in inducing PANoptosis, characterize PANoptosis as a novel form of cell death associated with mitotic catastrophe, and confirm the synergistic antitumor activity of RP-6306 and gemcitabine in PDAC. Moreover, GEM + RP-6306@BxPC-3M exhibits improved safety and enhanced antitumor efficacy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"526"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anoikis resistance in gastric cancer: a comprehensive review. 胃癌耐药研究综述

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07860-1

Teresa D'Amore, Daniele Bravoco, Giuseppina Di Paola, Francesco Albano, Mariarita Brancaccio, Claudia Sabato, Giuseppe Cesta, Cinzia Zolfanelli, Vincenzo Lauciello, Geppino Falco, Pellegrino Mazzone

{"title":"Anoikis resistance in gastric cancer: a comprehensive review.","authors":"Teresa D'Amore, Daniele Bravoco, Giuseppina Di Paola, Francesco Albano, Mariarita Brancaccio, Claudia Sabato, Giuseppe Cesta, Cinzia Zolfanelli, Vincenzo Lauciello, Geppino Falco, Pellegrino Mazzone","doi":"10.1038/s41419-025-07860-1","DOIUrl":"10.1038/s41419-025-07860-1","url":null,"abstract":"Gastric cancer (GC) is a predominant malignant neoplasia responsible for cancer death worldwide. Because of the difficulty in early diagnosis as well as its high metastasis rate, GC shows an increasing incidence and poor prognosis. Conventional treatments for GC, such as chemotherapy, radiotherapy, and surgical resection, still fail to achieve curative effects because of drug resistance, a mechanism that leads to a reduction of 5-year survival for GC patients. Anoikis, a particular type of programmed cell death, is activated upon cancer cell detachment from the extracellular matrix, playing a crucial role in antagonizing the progression of several malignant tumors. Because GC cells metastasize mainly in the nearby sites in the peritoneum, a better comprehension of the molecular mechanisms involved in the anchorage-independent growth as well as metastatic spreading is crucial to counteract GC progression. In this context, this review critically examines the molecular mechanisms of anoikis, key pathways and regulatory networks, and the role of anoikis resistance in GC. Furthermore, it summarizes potential therapeutic strategies for targeting anoikis-resistant cells. By collecting and analyzing existing literature, this work aims to bridge gaps in the comprehension of the relation between anoikis resistance and GC pathophysiology, providing novel insights and directions for future research in this field.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"528"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma. EZH2抑制剂SHR2554通过STAT1增强HDAC抑制剂Chidamide在t细胞淋巴瘤中的抗肿瘤作用。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-14 DOI: 10.1038/s41419-025-07775-x

Jiajin Wu, Dingyao Hu, Hui Yu, Dedao Wang, Yingying Ye, Jiaowu Cao, Tao Pan, Lan Mi, Yuqin Song, Meng Wu, Lingyan Ping, Jun Zhu

引用次数: 0

KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers. KDM6A下调通过激活增强子促进癌症相关成纤维细胞中肿瘤易感细胞因子的表达。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-14 DOI: 10.1038/s41419-025-07818-3

Jieying Zhang, Suoyu Xiang, Dan Liu, Xiaomeng Pei, Meng Chen, Yiheng Zhao, Yongbin Wang, Qiong Wang, Lan Kang, Zuoren Yu, Jun Mi, Wujun Xiong

{"title":"KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers.","authors":"Jieying Zhang, Suoyu Xiang, Dan Liu, Xiaomeng Pei, Meng Chen, Yiheng Zhao, Yongbin Wang, Qiong Wang, Lan Kang, Zuoren Yu, Jun Mi, Wujun Xiong","doi":"10.1038/s41419-025-07818-3","DOIUrl":"10.1038/s41419-025-07818-3","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are activated fibroblasts that secrete numerous cytokines and chemokines to accelerate tumor progression. However, the mechanism underlying cytokine production by CAFs remains unclear. This study reports that CAFs isolated from colon cancer tissue, TGF-β1-induced CAFs, or HCT116 co-cultured CAFs secrete more cytokines and growth factors represented by IGF1, ELN, and SFRP2. Mechanistic investigations demonstrate that aerobic glycolysis metabolites fumarate and succinate can induce the transcription of IGF1, ELN, and SFRP2 in CAFs, while α-ketoglutarate (α-KG) can antagonize the induction effect of fumarate and succinate. Moreover, the downregulation of KDM6A in CAFs is observed compared to quiescent fibroblasts (NAFs). Additionally, integrated analysis of ATAC sequencing and RNA sequencing revealed altered chromatin structure during fibroblast activation. CUT-tag sequencing and co-IP assays demonstrate that KDM6A is bound to WDR5, facilitating its association with the COMPASS complex and the polycomb repressive complex at the expected target loci. Depletion of KDM6A disrupts the homeostasis between polycomb and COMPASS complexes, leading to an increase in the expression of IGF1, ELN, and SFRP2. However, the inhibitor GSK-J4, specific for both KDM6A and KDM6B, reduces IGF1 expression, indicating that KDM6B compensates for the demethylase function of KDM6A but cannot replace KDM6A to maintain the homeostasis of COMPASS and polycomb repressive complexes. These findings suggest a metabolism-related epigenetic mechanism for cytokine expression, where reduced KDM6A levels enhance the tumor-promoting effect of CAFs. This may provide insights into why colon cancer is more prevalent in men than in women, since KDM6A is an X-chromosome-associated gene.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"523"},"PeriodicalIF":8.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0