AI Article Synopsis
- - CTCF is a key regulator of chromatin organization that is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and interacts with HNRNPU, which aids in the activation of IGF2BP2, promoting the proliferation of PDAC cells.
- - This activation leads to histone lactylation at the IGF2BP2 promoter, enhancing mRNA stability of critical oncogenes like CSF1 and MYC, and influencing alternative splicing to affect tumor-associated macrophages (TAMs).
- - The study suggests that CTCF's role in histone modifications, m6A methylation, and splicing could be targeted for immunotherapy in PDAC, with
Article 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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| http://dx.doi.org/10.1038/s41418-024-01423-1 | DOI Listing |
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