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

期刊论文
发表日期：

2024年11月30日

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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

摘要

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.