The modulation of PD-L1 induced by the oncogenic HBXIP for breast cancer growth.

Abstract

Programmed death ligand-1 (PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression. A tumor-promoting role for abundant PD-L1 in several cancers is revealed. However, the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure. Here, the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo. RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes, especially cancer development. In clinical breast cancer tissues and cells, PD-L1 and HBXIP are both increased, and their expressions are positively correlated. Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2. Specifically, HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300, leading to the stability of PD-L1 protein. Functionally, depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth. Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP. Collectively, the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.

• Authors: Fei-Fei Xu, Hui-Min Sun, Run-Ping Fang, Lu Zhang, Hui Shi, Xue Wang, Xue-Li Fu, Xian-Meng Li, Xu-He Shi, Yue Wu, Kai Ye, Wei-Ying Zhang, Li-Hong Ye
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 2 Pg. 429-445 (Feb 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 33824459 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Adaptor Proteins, Signal Transducing
• B7-H1 Antigen
• CD274 protein, human
• LAMTOR5 protein, human

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• B7-H1 Antigen (metabolism)
• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Chromatin Immunoprecipitation
• Female
• Fluorescent Antibody Technique
• Humans
• MCF-7 Cells
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction