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BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer

Oncogene (2025)Cite this article

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Abstract

Tumor-associated macrophages (TAMs) in the tumor microenvironment play a key role in drug resistance, but the mechanisms underlying TAM polarization and its role in drug resistance remain unclear. Here, we identified BRD4 as a critical factor in TAM polarization and drug resistance in colorectal cancer (CRC). BRD4 deficiency in macrophages impaired M2-like TAM polarization, and tumors from myeloid-lineage specific Brd4 conditional knockout (Brd4-CKO) mice displayed a reduction in infiltrating M2-like TAMs and an enhanced anti-tumor microenvironment. Colon cancer cells treated with conditioned medium from polarized Brd4-deficient TAMs, as well as tumors in Brd4-CKO mice, were more sensitive to oxaliplatin. RNA-seq and cytokine microarray analysis revealed that mRNA and protein levels of PAI-1 were significantly decreased in Brd4-deficient polarized TAMs. BRD4 was recruited to the promoter of Serpine1, promoting SMAD-dependent PAI-1 expression. Supplementing Brd4-deficient TAMs with recombinant PAI-1 hampered the sensitivity of colon cancer cells to oxaliplatin. Moreover, PAI-1 inhibitor and oxaliplatin synergistically suppressed the growth of colon tumors. Clinically, the expression levels of BRD4 in TAMs and PAI-1 in tumors were elevated in CRC patients with chemoresistance, correlating with shorter recurrence-free survival. Collectively, our findings uncover a novel role for BRD4 in TAM polarization and drug resistance via PAI-1 upregulation, suggesting the BRD4/PAI-1 axis as a potential prognostic marker and therapeutic target in CRC.

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Fig. 1: BRD4 regulates the polarization of TAMs and the immunosuppressive TME.
Fig. 2: Myeloid BRD4 deficiency enhances sensitivity of MC38 cells to oxaliplatin in vivo and in vitro.
Fig. 3: Deletion of BRD4 alters the transcriptional landscape in TAMs.
Fig. 4: BRD4 cooperates with SMAD3 to regulate PAI-1 expression in M2-like TAMs.
Fig. 5: BRD4-regulated PAI-1 in TAMs confer MC38 cell resistance to oxaliplatin.
Fig. 6: BRD4 levels in TAMs correlate with PAI-1 expression in tumor tissues of chemoresistant CRC patients.

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The data are available from the corresponding author upon request.

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Acknowledgements

We thank Cailing Yan from the Public Technology Service Center at Fujian Medical University for assistance with the IVIS® Spectrum In Vivo Imaging System analysis. This work was supported by the National Natural Science Foundation of China (81902842 to XMH and 81801974 to JFH), the Natural Science Foundation of Fujian Province (2022J01210 to DP, 2020J01615 to JFH and 2021J01669 to XMH), the Joint Funds for Innovation in Science and Technology, Fujian Province (2023Y9001 to XMH and 2020Y9006 to JFH), the Young and Middle-Aged Key Personnel Training Project of the Fujian Provincial Health Commission (2021GGA029 to DP); and the UIUC Research Board (RB24044) and CCIL Seed Grant to LFC.

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Author notes

  1. These authors contributed equally: Dun Pan, Jinfeng Hu, Guo Li.

Authors and Affiliations

  1. Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Basic Medical Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China

    Dun Pan, Jinfeng Hu, Guo Li, Xuming Gao, Jie Wang, Leisi Jiang, Hong Lin, Yulin Chen, Min Zheng & Xiangming Hu

  2. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China

    Dun Pan & Hui Chen

  3. Department of Biochemistry, College of Liberal Arts & Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Dun Pan, Yanheng Chen, Yiran Zheng & Lin-Feng Chen

  4. Public Technology Service Center, Fujian Medical University, Fuzhou, China

    Junjin Lin

  5. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Lin-Feng Chen

  6. Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA

    Lin-Feng Chen

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Contributions

XMH and LFC designed the experiment; DP, JFH, GL, XMG, JW, LSJ, HL, YLC, YRZ and YHC performed the experiments; XMH, DP, JFH, GL, JW, XMG, LSJ, HL, YLC, YHC, YRZ, JJL, MZ, HC, and LFC analyzed the data; XMH, LFC and HC supervised the research; DP, XMH and LFC wrote the manuscript.

Corresponding authors

Correspondence to Hui Chen, Lin-Feng Chen or Xiangming Hu.

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The authors declare no competing interests.

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All human tissue investigations in this study were conducted in accordance with protocols approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (MRCTA, ECFAH of FMU 2021-423). Informed consent was obtained from all patients prior to the use of tumor tissues and clinical data. All animal experiments were approved by the Institutional Animal Care and Use Committee of Fujian Medical University (IACUC FJMU 2023-Y-0652).

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Pan, D., Hu, J., Li, G. et al. BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer. Oncogene (2025). https://doi.org/10.1038/s41388-025-03453-6

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