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RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment
- Source :
- Molecular Cancer, Vol 20, Iss 1, Pp 1-20 (2021), Molecular Cancer
- Publication Year :
- 2021
- Publisher :
- BMC, 2021.
-
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.
- Subjects :
- Cancer Research
Cell signaling
TRIM28
Immunostimulatory cytokines
Necroptosis
medicine.medical_treatment
Biology
Tripartite Motif-Containing Protein 28
RIPK3
Models, Biological
NF-κB
Cell Line
Transactivation
Mice
Cancer immunotherapy
Neoplasms
medicine
Tumor Microenvironment
Animals
Humans
Transcription factor
RC254-282
Tumor microenvironment
Binding Sites
Cell Death
Research
NF-kappa B
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Chromatin
Cell biology
Gene Expression Regulation, Neoplastic
Oncology
Transcriptional regulator
Receptor-Interacting Protein Serine-Threonine Kinases
Cancer cell
Molecular Medicine
Cytokines
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer
- Accession number :
- edsair.doi.dedup.....fb047433c5ce71ab38855274170cd385