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.

Document Type

Article

Publication Date

2024

Notes/Citation Information

Copyright © 2024 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution- NonCommercial-NoDerivatives License 4.0 (CC BY- NC- ND).

Digital Object Identifier (DOI)

https://doi.org/10.1073/pnas.2307150121

Funding Information

This work was supported by grants from NIH (P20GM121327 and CA230758) to Y.W.

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