Zhang Jieying, Xiang Suoyu, Liu Dan, Pei Xiaomeng, Chen Meng, Zhao Yiheng, Wang Yongbin, Wang Qiong, Kang Lan, Yu Zuoren, Mi Jun, Xiong Wujun
Hongqiao International Institute of Medicine, Tongren Hospital; Basic Medical Institute; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Cell Death Dis. 2025 Jul 14;16(1):523. doi: 10.1038/s41419-025-07818-3.
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.
癌症相关成纤维细胞（CAFs）是活化的成纤维细胞，可分泌多种细胞因子和趋化因子以加速肿瘤进展。然而，CAFs产生细胞因子的潜在机制仍不清楚。本研究报告称，从结肠癌组织分离的CAFs、转化生长因子-β1诱导的CAFs或与HCT116共培养的CAFs分泌更多以胰岛素样生长因子1（IGF1）、弹力蛋白（ELN）和分泌型卷曲相关蛋白2（SFRP2）为代表的细胞因子和生长因子。机制研究表明，有氧糖酵解代谢产物富马酸和琥珀酸可诱导CAFs中IGF1、ELN和SFRP2的转录，而α-酮戊二酸（α-KG）可拮抗富马酸和琥珀酸的诱导作用。此外，与静止成纤维细胞（NAFs）相比，观察到CAFs中赖氨酸特异性去甲基化酶6A（KDM6A）的表达下调。此外，对转座酶可及染色质测序（ATAC测序）和RNA测序的综合分析揭示了成纤维细胞活化过程中染色质结构的改变。染色质切割标签测序（CUT-tag测序）和免疫共沉淀实验表明，KDM6A与WD重复结构域5（WDR5）结合，促进其在预期靶基因座与COMPASS复合物和多梳抑制复合物结合。KDM6A的缺失破坏了多梳复合物和COMPASS复合物之间的平衡，导致IGF1、ELN和SFRP2的表达增加。然而，对KDM6A和赖氨酸特异性去甲基化酶6B（KDM6B）均具有特异性的抑制剂GSK-J4可降低IGF1的表达，表明KDM6B可补偿KDM6A的去甲基化酶功能，但不能替代KDM6A来维持COMPASS和多梳抑制复合物的平衡。这些发现提示了一种与代谢相关的细胞因子表达表观遗传机制，其中KDM6A水平降低增强了CAFs的促肿瘤作用。这可能为结肠癌在男性中比在女性中更普遍提供了见解，因为KDM6A是一个与X染色体相关的基因。
