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Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis
- Source :
- Cell Discovery, Vol 9, Iss 1, Pp 1-19 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Publishing Group, 2023.
-
Abstract
- Abstract Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3–5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.
Details
- Language :
- English
- ISSN :
- 20565968
- Volume :
- 9
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Discovery
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.4c04d27191c4cfe826fe8c2c4438c17
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41421-023-00521-7