RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment
Abstract Background Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis...
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doaj-9649dec1a70f41ebb05ee81d7275fc5f2021-08-22T11:03:26ZengBMCMolecular Cancer1476-45982021-08-0120112010.1186/s12943-021-01399-3RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironmentHan-Hee Park0Hwa-Ryeon Kim1Sang-Yeong Park2Sung-Min Hwang3Sun Mi Hong4Sangwook Park5Ho Chul Kang6Michael J. Morgan7Jong-Ho Cha8Dakeun Lee9Jae-Seok Roe10You-Sun Kim11Department of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biochemistry, Ajou University School of MedicineDepartment of Biomedical Sciences, Graduate School, Ajou UniversityDepartment of Biomedical Sciences, Graduate School, Ajou UniversityDepartment of Natural Sciences, Northeastern State UniversityDepartment of Biomedical Sciences, College of Medicine, Inha UniversityDepartment of Pathology, Ajou University School of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Biochemistry, Ajou University School of MedicineAbstract Background Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes. Methods We employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8+ T cells or dendritic cells (DC) in all TCGA tumors. Results We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses. Conclusion Our data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.https://doi.org/10.1186/s12943-021-01399-3RIPK3TRIM28NF-κBTranscriptional regulatorChromatinImmunostimulatory cytokines |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Han-Hee Park Hwa-Ryeon Kim Sang-Yeong Park Sung-Min Hwang Sun Mi Hong Sangwook Park Ho Chul Kang Michael J. Morgan Jong-Ho Cha Dakeun Lee Jae-Seok Roe You-Sun Kim |
spellingShingle |
Han-Hee Park Hwa-Ryeon Kim Sang-Yeong Park Sung-Min Hwang Sun Mi Hong Sangwook Park Ho Chul Kang Michael J. Morgan Jong-Ho Cha Dakeun Lee Jae-Seok Roe You-Sun Kim RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment Molecular Cancer RIPK3 TRIM28 NF-κB Transcriptional regulator Chromatin Immunostimulatory cytokines |
author_facet |
Han-Hee Park Hwa-Ryeon Kim Sang-Yeong Park Sung-Min Hwang Sun Mi Hong Sangwook Park Ho Chul Kang Michael J. Morgan Jong-Ho Cha Dakeun Lee Jae-Seok Roe You-Sun Kim |
author_sort |
Han-Hee Park |
title |
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment |
title_short |
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment |
title_full |
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment |
title_fullStr |
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment |
title_full_unstemmed |
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment |
title_sort |
ripk3 activation induces trim28 derepression in cancer cells and enhances the anti-tumor microenvironment |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2021-08-01 |
description |
Abstract Background Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes. Methods We employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8+ T cells or dendritic cells (DC) in all TCGA tumors. Results We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses. Conclusion Our data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity. |
topic |
RIPK3 TRIM28 NF-κB Transcriptional regulator Chromatin Immunostimulatory cytokines |
url |
https://doi.org/10.1186/s12943-021-01399-3 |
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