RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization

Bo Dong, Xinzhao Wang, Xiang Song, Jianlin Wang, Xia Liu, Zhiyong Yu, Yongkun Zhou, Jiong Deng, Yadi Wu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus, and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

Original languageEnglish
Pages (from-to)e2307150121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number7
DOIs
StatePublished - Feb 13 2024

Keywords

  • CDK9
  • LSD1
  • RNF20
  • epigenetic
  • immunosuppression

ASJC Scopus subject areas

  • General

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