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Upregulation of IL-6 in CUL4B-deficient myeloid-derived suppressive cells increases the aggressiveness of cancer cells

Oncogene volume 38, pages 5860–5872 (2019)Cite this article

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Abstract

Cancer progression depends on a tumor-supportive microenvironment. Myeloid-derived suppressor cells (MDSCs) represent key cellular components in tumor microenvironment and have been demonstrated to facilitate tumor progression by restricting host immune responses and by sustaining the malignancy of cancer cells. CUL4B, which assembles the CUL4B-RING E3 ligase complex (CRL4B), possesses a potent oncogenic property in cancer cells by epigenetically inactivating many tumor suppressors. However, CUL4B in hematopoietic cells exerts tumor-suppressive effect by restricting the accumulation and function of MDSCs. How CUL4B regulates the function of MDSCs is not fully characterized. In the present study, we demonstrate that the enhanced growth and metastasis of transplanted tumor cells in hematopoietic or myeloid cell-specific Cul4b knockout recipient mice is mediated by increased production of IL-6 in MDSCs. CUL4B complex epigenetically represses IL-6 transcription in myeloid cells. The IL-6 produced by MDSCs renders cancer cells stem cell-like properties by activating IL-6/STAT3 signaling. This crosstalk was effectively blocked either by blocking IL-6 in MDSCs or by inhibition of STAT3 activation in tumor cells. These findings provide a new mechanistic insight into the cancer-promoting property of MDSCs.

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References

  1. Visvader JE. Cells of origin in cancer. Nature. 2011;469:314–22.

    Article  CAS  Google Scholar 

  2. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

    Article  CAS  Google Scholar 

  3. Umansky V, Sevko A. Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron. 2013;6:169–77.

    Article  CAS  Google Scholar 

  4. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8.

    Article  CAS  Google Scholar 

  5. Albini A, Bruno A, Noonan DM, Mortara L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. 2018;9:527.

    Article  Google Scholar 

  6. Safarzadeh E, Orangi M, Mohammadi H, Babaie F, Baradaran B. Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. J Cell Physiol. 2018;233:3024–36.

    Article  CAS  Google Scholar 

  7. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  Google Scholar 

  8. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618–31.

    Article  CAS  Google Scholar 

  9. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–20.

    Article  CAS  Google Scholar 

  10. Pastaki Khoshbin A, Eskian M, Keshavarz-Fathi M, Rezaei N. Roles of myeloid-derived suppressor cells in cancer metastasis: immunosuppression and beyond. Arch Immunol Ther Exp (Warsz). 2018;67:89–102.

    Article  Google Scholar 

  11. Hannah J, Zhou P. Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B. Gene. 2015;573:33–45.

    Article  CAS  Google Scholar 

  12. Jia L, Yan F, Cao W, Chen Z, Zheng H, Li H, et al. Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer. J Biol Chem. 2017;292:2966–78.

    Article  CAS  Google Scholar 

  13. Hu H, Yang Y, Ji Q, Zhao W, Jiang B, Liu R, et al. CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis. Cancer Cell. 2012;22:781–95.

    Article  CAS  Google Scholar 

  14. Yuan J, Han B, Hu H, Qian Y, Liu Z, Wei Z, et al. CUL4B activates Wnt/beta-catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists. J Pathol. 2015;235:784–95.

    Article  CAS  Google Scholar 

  15. Yang Y, Liu R, Qiu R, Zheng Y, Huang W, Hu H, et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene. 2015;34:104–18.

    Article  Google Scholar 

  16. Jiang T, Tang HM, Wu ZH, Chen J, Lu S, Zhou CZ, et al. Cullin 4B is a novel prognostic marker that correlates with colon cancer progression and pathogenesis. Med Oncol. 2013;30:534.

    Article  Google Scholar 

  17. Mi J, Zou Y, Lin X, Lu J, Liu X, Zhao H, et al. Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma. Mol Oncol. 2017;11:305–19.

    Article  CAS  Google Scholar 

  18. Ji Q, Hu H, Yang F, Yuan J, Yang Y, Jiang L, et al. CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression. J Cell Sci. 2014;127:4679–91.

    Article  Google Scholar 

  19. Qian Y, Yuan J, Hu H, Yang Q, Li J, Zhang S, et al. The CUL4B/AKT/beta-catenin axis restricts the accumulation of myeloid-derived suppressor cells to prohibit the establishment of a tumor-permissive microenvironment. Cancer Res. 2015;75:5070–83.

    Article  CAS  Google Scholar 

  20. Peng D, Tanikawa T, Li W, Zhao L, Vatan L, Szeliga W, et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 2016;76:3156–65.

    Article  CAS  Google Scholar 

  21. He YM, Xiao YS, Wei L, Zhang JQ, Peng CH. CUL4B promotes metastasis and proliferation in pancreatic cancer cells by inducing epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway. J Cell Biochem. 2018;119:5308–23.

    Article  CAS  Google Scholar 

  22. Chen Z, Wang K, Hou C, Jiang K, Chen B, Chen J, et al. CRL4B(DCAF11) E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells. Sci Rep. 2017;7:1175.

    Article  Google Scholar 

  23. Chin AR, Wang SE. Cytokines driving breast cancer stemness. Mol Cell Endocrinol. 2014;382:598–602.

    Article  CAS  Google Scholar 

  24. Wang SW, Sun YM. The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncol. 2014;44:1032–40.

    Article  CAS  Google Scholar 

  25. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48.

    Article  CAS  Google Scholar 

  26. Xiong S, Wang R, Chen Q, Luo J, Wang J, Zhao Z, et al. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res. 2018;8:302–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kishimoto T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol. 2005;23:1–21.

    Article  CAS  Google Scholar 

  28. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.

    Article  CAS  Google Scholar 

  29. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51.

    Article  CAS  Google Scholar 

  30. Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–35.

    Article  CAS  Google Scholar 

  31. Dandrea M, Donadelli M, Costanzo C, Scarpa A, Palmieri M. MeCP2/H3meK9 are involved in IL-6 gene silencing in pancreatic adenocarcinoma cell lines. Nucleic Acids Res. 2009;37:6681–90.

    Article  CAS  Google Scholar 

  32. Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008;58:2686–93.

    Article  Google Scholar 

  33. Ishida K, Kobayashi T, Ito S, Komatsu Y, Yokoyama T, Okada M, et al. Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. J Periodontol. 2012;83:917–25.

    Article  CAS  Google Scholar 

  34. Tang B, Zhao R, Sun Y, Zhu Y, Zhong J, Zhao G, et al. Interleukin-6 expression was regulated by epigenetic mechanisms in response to influenza virus infection or dsRNA treatment. Mol Immunol. 2011;48:1001–8.

    Article  CAS  Google Scholar 

  35. Jiang B, Zhao W, Yuan J, Qian Y, Sun W, Zou Y, et al. Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development. PLoS ONE. 2012;7:e37070.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81330050 and 81571523), the Natural Science Foundation of Shandong Province (ZR2016HZ01), and the Key Research and Development Program of Shandong Province (2016ZDJS07A08).

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Authors and Affiliations

  1. Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China

    Zhiliang Xu, Linchuan Li, Yanyan Qian, Yu Song, Liping Qin, Yuyao Duan, Molin Wang, Peishan Li, Baichun Jiang & Yaoqin Gong

  2. Key Laboratory of Experimental Teratology, Ministry of Education, Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China

    Chunhong Ma

  3. State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China

    Changshun Shao

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  1. Zhiliang Xu
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Xu, Z., Li, L., Qian, Y. et al. Upregulation of IL-6 in CUL4B-deficient myeloid-derived suppressive cells increases the aggressiveness of cancer cells. Oncogene 38, 5860–5872 (2019). https://doi.org/10.1038/s41388-019-0847-x

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