机构：[1]Hongqiao International Institute of Medicine, Tongren Hospital[2]Basic Medical Institute[3]Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[4]Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.[5]Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.[6]Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.[7]Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
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-beta 1-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 alpha-ketoglutarate (alpha-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.
基金：
the Shanghai Committee of Science and Technology (11DZ2260200) and the
National Natural Science Foundation of China (82073040) (81872342) to Dr. Mi. The
Clinical Medicine Emerging Specialty (or Specific Disease) Program of the Pudong
New Area Health Commission (2025-PWXZ-05) and Science and Technology
Development Fund of Shanghai Pudong New Area (PKJ2024-Y54)
第一作者机构：[1]Hongqiao International Institute of Medicine, Tongren Hospital[2]Basic Medical Institute[3]Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[4]Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
共同第一作者：
通讯作者：
通讯机构：[1]Hongqiao International Institute of Medicine, Tongren Hospital[2]Basic Medical Institute[3]Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
推荐引用方式(GB/T 7714)：
Zhang Jieying,Xiang Suoyu,Liu Dan,et al.KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers[J].CELL DEATH & DISEASE.2025,16(1):doi:10.1038/s41419-025-07818-3.
APA：
Zhang, Jieying,Xiang, Suoyu,Liu, Dan,Pei, Xiaomeng,Chen, Meng...&Xiong, Wujun.(2025).KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers.CELL DEATH & DISEASE,16,(1)
MLA：
Zhang, Jieying,et al."KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers".CELL DEATH & DISEASE 16..1(2025)
生物学