RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment

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

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


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.

Original languageEnglish
Article number107
JournalMolecular Cancer
Issue number1
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea to YS.K. (grant number 2017R1A2B3002343 and 2021R1A4A1031856) and the Brain Korea 21 FOUR program for Leading Universities & Students supported by the Korean government (to HR.K. and JS.R.), and INHA UNIVERSITY Research Grant (to JH. C).

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research


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