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CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling

Oncogene volume 34, pages 177–187 (2015)Cite this article

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Abstract

Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

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Acknowledgements

This work was supported in part by grants of the European Commisson FP7 grant (Collaborative Project ‘EPC-TM-Net, to PM, AN and TMG), Deutsche Forschungsgemeinschaft (DFG) (to PM), the LOEWE initiative of the state of Hessen, the Behring-Roentgen Foundation (to PM) and the Deutsche Krebshilfe (to PM). This publication reflects only the authors’ views. The European Community is not liable for any use that may be made of the information herein. We thank Dr Pietro DiFazio, Dept. of Experimental Surgery, for his help with FACS analyses.

Financial support: This work was supported in part by grants of the European Commisson FP7 grant (Collaborative Project ‘EPC-TM-Net, to PM, AN and TMG), Deutsche Forschungsgemeinschaft (DFG) (to PM), the LOEWE initiative of the state of Hessen, the Behring-Roentgen Foundation (to PM), and the Deutsche Krebshilfe (to PM). This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

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  1. Department of Gastroenterology and Endocrinology, University Hospital, Philipps University, Marburg, Germany

    B Kühnemuth, L Mühlberg, H Griesmann, A Neesse, N Milosevic, T Wissniowski, M Buchholz, T M Gress & P Michl

  2. Department of Biology, Philipps University, School of Medicine, Marburg, Germany

    M Schipper

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  1. B Kühnemuth
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Kühnemuth, B., Mühlberg, L., Schipper, M. et al. CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling. Oncogene 34, 177–187 (2015). https://doi.org/10.1038/onc.2013.530

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