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

Cell Death & Differentiation volume 32, pages 745–762 (2025)Cite this article

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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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Fig. 1: CTCF promotes the progression of pancreatic cancer.
Fig. 2: CTCF recruits HNRNPU to activate IGF2BP2 transcription.
Fig. 3: CTCF activates histone lactylation modifications via FLG-AS1-mediated recruitment of EP300.
Fig. 4: FLG-AS1 interacts with IGF2BP2 to enhance the mRNA stability of CSF1 in an m6A-dependent manner.
Fig. 5: HNRNPU interacts with FLG-AS1 to control exon skipping of CSF1 in PCs.
Fig. 6: CTCF drives M2 macrophage polarization via the CSF1-CSF1R pathway to facilitate PDAC proliferation.
Fig. 7: Curaxin inhibits M2 macrophage polarization to reduce PDAC growth.
Fig. 8: Curaxin sensitizes PDAC to gemcitabine therapy in mice models.

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Data availability

Data are available in a public, open access repository. All sequencing data generated in this study are deposited at Mendeley Data, https://doi.org/10.17632/hzjwhm46 and https://doi.org/10.17632/7fkktknnm8.1. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Information.

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Acknowledgements

Thanks for the sequencing service provided by the Shanghai Bioegene Co., Ltd.

Funding

This work was sponsored by The National Natural Science Foundation of China (81871906 and 82073326), Basic Research Program of Shanghai (20JC1412200), the National Key Research and Development Program of China (2020YFA0113000) and PostGraduate Innovation Fund of Interdiscipline and New Medicine from School of Medicine of Shanghai University.

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  1. These authors contributed equally: Yihao Liu, Pengyi Liu, Songqi Duan, Jiayu Lin.

Authors and Affiliations

  1. Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Yihao Liu, Pengyi Liu, Jiayu Lin, Jia Liu, Jiewei Lin, Shuyu Zhai, Kai Qin, Yizhi Cao, Jingwei Li, Yang Liu, Mengmin Chen, Siyi Zou, Chenlei Wen, Da Fu, Jiancheng Wang, Haili Bao, Keyan Sun, Yu Jiang & Baiyong Shen

  2. Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yihao Liu, Pengyi Liu, Jiayu Lin, Zhengwei Yu, Xia Gao, Xiuqiao Sun, Jia Liu, Jiewei Lin, Shuyu Zhai, Kai Qin, Yizhi Cao, Jingwei Li, Yang Liu, Mengmin Chen, Siyi Zou, Chenlei Wen, Da Fu, Jiancheng Wang, Keyan Sun, Yu Jiang & Baiyong Shen

  3. State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China

    Yihao Liu, Pengyi Liu, Jiayu Lin, Jia Liu, Jiewei Lin, Shuyu Zhai, Kai Qin, Yizhi Cao, Jingwei Li, Yang Liu, Mengmin Chen, Siyi Zou, Chenlei Wen, Da Fu, Jiancheng Wang, Keyan Sun, Yu Jiang & Baiyong Shen

  4. College of Food Science, Sichuan Agricultural University, Yaan, China

    Songqi Duan

  5. School of Life Sciences, Shanghai University, Shanghai, China

    Wenxin Qi & Jiao Wang

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  1. Yihao Liu
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Contributions

YH Liu designed experiments and drafted manuscripts; YH Liu, PY Liu, JY Lin, WX Qi, Y Liu, Y Jiang, ZW Yu, X Gao, XQ Sun, J Liu, JW Lin, SY Zhai, YZ Cao, K Qin and JW Li conducted experiments; YH Liu, PY Liu, JY Lin, Y Jiang, MM Chen, SY Zou, CL Wen, HL Bao and KY Sun were responsible for sample collection; SQ Duan, D Fu and JC Wang was responsible for data analysis; J Wang, Y Jiang, KY Sun, HL Bao and BY Shen discussed and revised the manuscript. All authors approved the manuscript.

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Correspondence to Haili Bao, Keyan Sun, Yu Jiang or Baiyong Shen.

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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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Liu, Y., Liu, P., Duan, S. et al. CTCF enhances pancreatic cancer progression via FLG-AS1-dependent epigenetic regulation and macrophage polarization. Cell Death Differ 32, 745–762 (2025). https://doi.org/10.1038/s41418-024-01423-1

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