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，并在胰腺导管腺癌 （PDAC） 中上调。我们发现 CTCF 通过 FLG-AS1 依赖性机制与 HNRNPU 相互作用，促进 EP300 的募集和 m6A reader IGF2BP2的激活。这种激活促进 IGF2BP2 启动子区域的组蛋白乳酸化，刺激 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 的选择性剪接，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 和选择性注射的致癌修饰作为 PDAC 中 TAMs 重编程的多调节模式，并确定 CTCF 是 PDAC 免疫治疗的潜在治疗靶点，其抑制 M2 通过 IGF2BP2/CSF1/CSF1R 轴极化。Curaxin 联合吉西他滨治疗已显示出对 PDAC 的良好抗肿瘤疗效。