KDM5 histone demethylases repress immune response via suppression of STING
| Autor: | Ajit Jadhav, Lizhen Wu, Daniel J. Jansen, Xin Hu, Mark J. Henderson, David J. Maloney, John R. Horton, Jian Cao, Stephen C. Kales, Bryan T. Mott, Anton Simeonov, Qin Yan, Shu Zhu, Wesley L. Cai, Gerald S. Shadel, Zongzhi Liu, Jocelyn F. Chen, Meiling Zhang, Xiaodong Cheng, Katherine Pohida, Ganesha Rai, Akiko Iwasaki, Sabine Lang, Matthew D. Hall |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Jumonji Domain-Containing Histone Demethylases medicine.medical_treatment Cancer Treatment Pathology and Laboratory Medicine Biochemistry Histones White Blood Cells Cytosol Cancer immunotherapy Animal Cells Medicine and Health Sciences Small interfering RNAs Biology (General) Immune Response Histone Demethylases T Cells General Neuroscience Nuclear Proteins Poxviruses Vaccinia Virus 3. Good health Nucleic acids Oncology Medical Microbiology Stimulator of interferon genes Viral Pathogens Viruses Histone Methyltransferases MCF-7 Cells Immunotherapy Pathogens Cellular Types General Agricultural and Biological Sciences Signal Transduction Research Article QH301-705.5 Immune Cells Immunology Biology Microbiology General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Immune system DNA-binding proteins medicine Genetics Humans Non-coding RNA Microbial Pathogens Innate immune system Blood Cells General Immunology and Microbiology Organisms Cancer Membrane Proteins Biology and Life Sciences Proteins DNA Reverse Transcription Cell Biology medicine.disease eye diseases Immunity Innate Gene regulation Repressor Proteins Sting 030104 developmental biology Cancer research RNA Interferons Gene expression DNA viruses |
| Zdroj: | PLoS Biology PLoS Biology, Vol 16, Iss 8, p e2006134 (2018) |
| ISSN: | 1545-7885 |
| Popis: | Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8+ T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy. Author summary Pathogens often find ways to turn down cell-intrinsic antipathogen immune responses by the host. Similarly, cancer cells use various mechanisms to evade attack by immune cells. One of the common mechanisms is suppression of the stimulator of interferon genes (STING)-dependent innate immune response. Using potent and specific small-molecule inhibitors and genetic-depletion approaches, we found that the silenced STING pathway can be reactivated in breast cancer cells by suppressing KDM5 demethylases. Activation of the STING pathway led to a robust interferon response, which blocked viral infection, and was associated with increased tumor-infiltrated lymphocytes and better patient survival in multiple cancer types. This discovery has major clinical implications for treating both pathogen infection and cancer because KDM5 inhibition provides a fast, robust, and reversible control of innate immune response. Since the discovery of histone demethylase activity of KDM5 proteins a decade ago, significant efforts have been dedicated to developing KDM5 inhibitors for clinical applications. In fact, a KDM5 inhibitor recently entered phase I clinical trial for treatment of hepatitis B infection. Here, we provide mechanistic insights on how KDM5 inhibitors block viral infection. Moreover, our results suggest that KDM5 inhibitors can also be combined with other cancer immunotherapies. |
| Databáze: | OpenAIRE |
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