Liu Yihao, Liu Pengyi, Duan Songqi, Lin Jiayu, Qi Wenxin, Yu Zhengwei, Gao Xia, Sun Xiuqiao, Liu Jia, Lin Jiewei, Zhai Shuyu, Qin Kai, Cao Yizhi, Li Jingwei, Liu Yang, Chen Mengmin, Zou Siyi, Wen Chenlei, Wang Jiao, Fu Da, Wang Jiancheng, Bao Haili, Sun Keyan, Jiang Yu, Shen Baiyong
Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Cell Death Differ. 2025 Apr;32(4):745-762. doi: 10.1038/s41418-024-01423-1. Epub 2024 Nov 30.
CCCTC-binding factor (CTCF) regulates chromatin organization and is upregulated in pancreatic ductal adenocarcinoma (PDAC). We found that CTCF interacts with HNRNPU through a FLG-AS1-dependent mechanism, facilitating the recruitment of EP300 and activation of the m6A reader IGF2BP2. This activation promotes histone lactylation at the promoter region of IGF2BP2 stimulating the proliferation of PDAC cells. IGF2BP2 enhanced the mRNA stability of CSF1 and MYC. Moreover, FLG-AS1 directly interacts with HNRNPU to modulate alternative splicing of CSF1, thus promoting the M2 polarization of tumor associated macrophages (TAMs) in PDAC. The results indicated that CTCF-induced oncogenic modification of histone lactylation, m6A and alternative spilcing as multi-regulation modes of TAMs reprogramming in PDAC and identifies CTCF as a potential therapeutic target for PDAC immunotherapy whose inhibition M2 polarization through the IGF2BP2/CSF1/CSF1R axis. Curaxin combined with gemcitabine treatment has shown promising antitumor efficacy against PDAC.
CCCTC结合因子（CTCF）调节染色质组织，且在胰腺导管腺癌（PDAC）中上调。我们发现CTCF通过一种依赖FLG-AS1的机制与HNRNPU相互作用，促进EP300的募集以及m6A阅读蛋白IGF2BP2的激活。这种激活促进了IGF2BP2启动子区域的组蛋白乳酸化，刺激了PDAC细胞的增殖。IGF2BP2增强了CSF1和MYC的mRNA稳定性。此外，FLG-AS1直接与HNRNPU相互作用以调节CSF1的可变剪接，从而促进PDAC中肿瘤相关巨噬细胞（TAM）的M2极化。结果表明，CTCF诱导的组蛋白乳酸化、m6A和可变剪接的致癌修饰是PDAC中TAM重编程的多种调节模式，并确定CTCF是PDAC免疫治疗的潜在治疗靶点，其通过IGF2BP2/CSF1/CSF1R轴抑制M2极化。Curaxin联合吉西他滨治疗已显示出对PDAC有前景的抗肿瘤疗效。
