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Title: KDM5 histone demethylases repress immune response via suppression of STING

Abstract

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 treatmentmore » and anticancer immunotherapy.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [1];  [1];  [1];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [4];  [5] more »;  [3];  [2];  [6];  [1];  [7] « less
  1. Yale School of Medicine, New Haven, CT (United States)
  2. The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  3. National inst. of Health, Rockville, MD (United States)
  4. Univ. of Science and Technology of China, Hefei (China)
  5. Yale School of Medicine, New Haven, CT (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
  6. Yale School of Medicine, New Haven, CT (United States); Salk Inst. for Biological Studies, La Jolla, CA (United States)
  7. New York Univ. (NYU), NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
American Cancer Society; Department of Defense Breast Cancer Research Program; National Inst. of Health; National Science Foundation (NSF)
OSTI Identifier:
1474177
Grant/Contract Number:  
RSG-13-384-01-DMC; W81XWH-14-1-0308; R21 CA187862; R21 CA191548; P30 CA16359; R01 GM114306; R01 AR069876; HHSN261200800001E; DGE-1122492; RR160029
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS biology (Online)
Additional Journal Information:
Journal Volume: 16; Journal Issue: 8; Journal ID: ISSN 1545-7885
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; interferons; small interfering RNAs; immune response; vaccinia virus; cancer treatment; reverse transcription; histones; T cells

Citation Formats

Wu, Lizhen, Cao, Jian, Cai, Wesley L., Lang, Sabine M., Horton, John R., Jansen, Daniel J., Liu, Zongzhi Z., Chen, Jocelyn F., Zhang, Meiling, Mott, Bryan T., Pohida, Katherine, Rai, Ganesha, Kales, Stephen C., Henderson, Mark J., Hu, Xin, Jadhav, Ajit, Maloney, David J., Simeonov, Anton, Zhu, Shu, Iwasaki, Akiko, Hall, Matthew D., Cheng, Xiaodong, Shadel, Gerald S., Yan, Qin, and Cadwell, Ken. KDM5 histone demethylases repress immune response via suppression of STING. United States: N. p., 2018. Web. doi:10.1371/journal.pbio.2006134.
Wu, Lizhen, Cao, Jian, Cai, Wesley L., Lang, Sabine M., Horton, John R., Jansen, Daniel J., Liu, Zongzhi Z., Chen, Jocelyn F., Zhang, Meiling, Mott, Bryan T., Pohida, Katherine, Rai, Ganesha, Kales, Stephen C., Henderson, Mark J., Hu, Xin, Jadhav, Ajit, Maloney, David J., Simeonov, Anton, Zhu, Shu, Iwasaki, Akiko, Hall, Matthew D., Cheng, Xiaodong, Shadel, Gerald S., Yan, Qin, & Cadwell, Ken. KDM5 histone demethylases repress immune response via suppression of STING. United States. doi:10.1371/journal.pbio.2006134.
Wu, Lizhen, Cao, Jian, Cai, Wesley L., Lang, Sabine M., Horton, John R., Jansen, Daniel J., Liu, Zongzhi Z., Chen, Jocelyn F., Zhang, Meiling, Mott, Bryan T., Pohida, Katherine, Rai, Ganesha, Kales, Stephen C., Henderson, Mark J., Hu, Xin, Jadhav, Ajit, Maloney, David J., Simeonov, Anton, Zhu, Shu, Iwasaki, Akiko, Hall, Matthew D., Cheng, Xiaodong, Shadel, Gerald S., Yan, Qin, and Cadwell, Ken. Mon . "KDM5 histone demethylases repress immune response via suppression of STING". United States. doi:10.1371/journal.pbio.2006134. https://www.osti.gov/servlets/purl/1474177.
@article{osti_1474177,
title = {KDM5 histone demethylases repress immune response via suppression of STING},
author = {Wu, Lizhen and Cao, Jian and Cai, Wesley L. and Lang, Sabine M. and Horton, John R. and Jansen, Daniel J. and Liu, Zongzhi Z. and Chen, Jocelyn F. and Zhang, Meiling and Mott, Bryan T. and Pohida, Katherine and Rai, Ganesha and Kales, Stephen C. and Henderson, Mark J. and Hu, Xin and Jadhav, Ajit and Maloney, David J. and Simeonov, Anton and Zhu, Shu and Iwasaki, Akiko and Hall, Matthew D. and Cheng, Xiaodong and Shadel, Gerald S. and Yan, Qin and Cadwell, Ken},
abstractNote = {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.},
doi = {10.1371/journal.pbio.2006134},
journal = {PLoS biology (Online)},
issn = {1545-7885},
number = 8,
volume = 16,
place = {United States},
year = {2018},
month = {8}
}

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