Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons

Yanan Liu, Longmiao Hu, Zhengzhen Wu, Kun Yuan, Guangliang Hong, Zhengke Lian, Juanjuan Feng, Na Li, Dali Li, Jiemin Wong, Jiekai Chen, Mingyao Liu, Jiangping He () and Xiufeng Pang ()
Additional contact information
Yanan Liu: East China Normal University
Longmiao Hu: East China Normal University
Zhengzhen Wu: East China Normal University
Kun Yuan: East China Normal University
Guangliang Hong: Guangzhou Laboratory
Zhengke Lian: East China Normal University
Juanjuan Feng: East China Normal University
Na Li: East China Normal University
Dali Li: East China Normal University
Jiemin Wong: East China Normal University
Jiekai Chen: Chinese Academy of Sciences
Mingyao Liu: East China Normal University
Jiangping He: Guangzhou Laboratory
Xiufeng Pang: East China Normal University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Immunotherapy has become established as major treatment modality for multiple types of solid tumors, including colorectal cancer. Identifying novel immunotherapeutic targets to enhance anti-tumor immunity and sensitize current immune checkpoint blockade (ICB) in colorectal cancer is needed. Here we report the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone methyl marks, as an essential mediator of immune escape. Ablation the function of PHF8 abrogates tumor growth, activates anti-tumor immune memory, and augments sensitivity to ICB therapy in mouse models of colorectal cancer. Strikingly, tumor PHF8 deletion stimulates a viral mimicry response in colorectal cancer cells, where the depletion of key components of endogenous nucleic acid sensing diminishes PHF8 loss-meditated antiviral immune responses and anti-tumor effects in vivo. Mechanistically, PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of the H3K9 methyltransferase SETDB1 in a demethylase-independent manner. Moreover, PHF8 expression is anti-correlated with canonical immune signatures and antiviral immune responses in human colorectal adenocarcinoma. Overall, our study establishes PHF8 as an epigenetic checkpoint, and targeting PHF8 is a promising viral mimicry-inducing approach to enhance intrinsic anti-tumor immunity or to conquer immune resistance.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-39943-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39943-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-39943-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().