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 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.

• Authors: 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
• Journal: Molecular cancer (Mol Cancer) Vol. 20 Issue 1 Pg. 107 (08 21 2021) ISSN: 1476-4598 [Electronic] England
• PMID: 34419074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Cytokines
• NF-kappa B
• TRIM28 protein, human
• Tripartite Motif-Containing Protein 28
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Animals
• Binding Sites
• Cell Death
• Cell Line
• Cytokines (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Models, Biological
• NF-kappa B (metabolism)
• Necroptosis
• Neoplasms (genetics, metabolism)
• Protein Binding
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Tripartite Motif-Containing Protein 28 (genetics)
• Tumor Microenvironment (genetics)