KDM5 histone demethylases repress immune response via suppression of STING.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-08-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.2006134 |
| _version_ | 1817995295525437440 |
|---|---|
| author | Lizhen Wu Jian Cao Wesley L Cai Sabine M Lang John R Horton Daniel J Jansen Zongzhi Z Liu Jocelyn F Chen Meiling Zhang Bryan T Mott Katherine Pohida Ganesha Rai Stephen C Kales Mark J Henderson Xin Hu Ajit Jadhav David J Maloney Anton Simeonov Shu Zhu Akiko Iwasaki Matthew D Hall Xiaodong Cheng Gerald S Shadel Qin Yan |
| author_facet | Lizhen Wu Jian Cao Wesley L Cai Sabine M Lang John R Horton Daniel J Jansen Zongzhi Z Liu Jocelyn F Chen Meiling Zhang Bryan T Mott Katherine Pohida Ganesha Rai Stephen C Kales Mark J Henderson Xin Hu Ajit Jadhav David J Maloney Anton Simeonov Shu Zhu Akiko Iwasaki Matthew D Hall Xiaodong Cheng Gerald S Shadel Qin Yan |
| author_sort | Lizhen Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T02:03:55Z |
| format | Article |
| id | doaj.art-b82bd2d7d5a04000a7a64e580355ce3f |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-14T02:03:55Z |
| publishDate | 2018-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-b82bd2d7d5a04000a7a64e580355ce3f2022-12-22T02:18:45ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852018-08-01168e200613410.1371/journal.pbio.2006134KDM5 histone demethylases repress immune response via suppression of STING.Lizhen WuJian CaoWesley L CaiSabine M LangJohn R HortonDaniel J JansenZongzhi Z LiuJocelyn F ChenMeiling ZhangBryan T MottKatherine PohidaGanesha RaiStephen C KalesMark J HendersonXin HuAjit JadhavDavid J MaloneyAnton SimeonovShu ZhuAkiko IwasakiMatthew D HallXiaodong ChengGerald S ShadelQin YanCyclic 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.https://doi.org/10.1371/journal.pbio.2006134 |
| spellingShingle | Lizhen Wu Jian Cao Wesley L Cai Sabine M Lang John R Horton Daniel J Jansen Zongzhi Z Liu Jocelyn F Chen Meiling Zhang Bryan T Mott Katherine Pohida Ganesha Rai Stephen C Kales Mark J Henderson Xin Hu Ajit Jadhav David J Maloney Anton Simeonov Shu Zhu Akiko Iwasaki Matthew D Hall Xiaodong Cheng Gerald S Shadel Qin Yan KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biology |
| title | KDM5 histone demethylases repress immune response via suppression of STING. |
| title_full | KDM5 histone demethylases repress immune response via suppression of STING. |
| title_fullStr | KDM5 histone demethylases repress immune response via suppression of STING. |
| title_full_unstemmed | KDM5 histone demethylases repress immune response via suppression of STING. |
| title_short | KDM5 histone demethylases repress immune response via suppression of STING. |
| title_sort | kdm5 histone demethylases repress immune response via suppression of sting |
| url | https://doi.org/10.1371/journal.pbio.2006134 |
| work_keys_str_mv | AT lizhenwu kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT jiancao kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT wesleylcai kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT sabinemlang kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT johnrhorton kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT danieljjansen kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT zongzhizliu kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT jocelynfchen kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT meilingzhang kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT bryantmott kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT katherinepohida kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT ganesharai kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT stephenckales kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT markjhenderson kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT xinhu kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT ajitjadhav kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT davidjmaloney kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT antonsimeonov kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT shuzhu kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT akikoiwasaki kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT matthewdhall kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT xiaodongcheng kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT geraldsshadel kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting AT qinyan kdm5histonedemethylasesrepressimmuneresponseviasuppressionofsting |