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

Yihao Liu; Pengyi Liu; Songqi Duan; Jiayu Lin; Wenxin Qi; 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; Jiao Wang; Da Fu; Jiancheng Wang; Haili Bao; Keyan Sun; Yu Jiang; Baiyong Shen

doi:10.1038/s41418-024-01423-1

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

Cell Death Differ. 2024 Nov 30. doi: 10.1038/s41418-024-01423-1. Online ahead of print.

Authors

Yihao Liu^#^{1

2

3}, Pengyi Liu^#^{1

2

3}, Songqi Duan^#⁴, Jiayu Lin^#^{1

2

3}, Wenxin Qi⁵, Zhengwei Yu², Xia Gao², Xiuqiao Sun², 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 Wang⁵, Da Fu^{1

2

3}, Jiancheng Wang^{1

2

3}, Haili Bao⁶, Keyan Sun^{7

8

9}, Yu Jiang^{10

11

12}, Baiyong Shen^{13

14

15}

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.
² Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China.
⁴ College of Food Science, Sichuan Agricultural University, Yaan, China.
⁵ School of Life Sciences, Shanghai University, Shanghai, China.
⁶ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. harryb139@gmail.com.
⁷ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. 188025796@qq.com.
⁸ Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China. 188025796@qq.com.
⁹ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China. 188025796@qq.com.
¹⁰ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. jiangyu890401@163.com.
¹¹ Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China. jiangyu890401@163.com.
¹² State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China. jiangyu890401@163.com.
¹³ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. shenby@shsmu.edu.cn.
¹⁴ Research Institute of Pancreatic Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China. shenby@shsmu.edu.cn.
¹⁵ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China. shenby@shsmu.edu.cn.

^# Contributed equally.

PMID: 39616247
DOI: 10.1038/s41418-024-01423-1

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.

Abstract

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