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. 2025 Apr;32(4):745-762.
doi: 10.1038/s41418-024-01423-1. Epub 2024 Nov 30.

CTCF enhances pancreatic cancer progression via FLG-AS1-dependent epigenetic regulation and macrophage polarization

Yihao Liu #  1   2   3 , Pengyi Liu #  1   2   3 , Songqi Duan #  4 , Jiayu Lin #  1   2   3 , Wenxin Qi  5 , Zhengwei Yu  2 , Xia Gao  2 , Xiuqiao Sun  2 , Jia Liu  1   2   3 , Jiewei Lin  1   2   3 , Shuyu Zhai  1   2   3 , Kai Qin  1   2   3 , Yizhi Cao  1   2   3 , Jingwei Li  1   2   3 , Yang Liu  1   2   3 , Mengmin Chen  1   2   3 , Siyi Zou  1   2   3 , Chenlei Wen  1   2   3 , Jiao Wang  5 , Da Fu  1   2   3 , Jiancheng Wang  1   2   3 , Haili Bao  6 , Keyan Sun  7   8   9 , Yu Jiang  10   11   12 , Baiyong Shen  13   14   15
Affiliations

CTCF enhances pancreatic cancer progression via FLG-AS1-dependent epigenetic regulation and macrophage polarization

Yihao Liu et al. Cell Death Differ. 2025 Apr.

Abstract

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Sample collections were approved by Ethnics Committee of Ruijin Hospital, Shanghai Jiaotong University School of Medicine (2021 Clinical Ethnics Review No. 161). Also, the animal research was authorized by the Shanghai Municipal Science and Technology Commission of Shanghai, China (SYXK-2018-0027). The informed consents were obtained from patients or their guardians, as appropriate. All methods were performed in accordance with the relevant guidelines and regulations.

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