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

• Published in: Acta pharmacologica Sinica Vol. 43; no. 2; pp. 429 - 445
• Main Authors: Xu, Fei-fei, Sun, Hui-min, Fang, Run-ping, Zhang, Lu, Shi, Hui, Wang, Xue, Fu, Xue-li, Li, Xian-meng, Shi, Xu-he, Wu, Yue, Ye, Kai, Zhang, Wei-ying, Ye, Li-hong
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.02.2022; Nature Publishing Group
• Subjects: Acetylation; Acetyltransferase; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Aspirin; B7-H1 Antigen - metabolism; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Ets-2 protein; Female; Fluorescent Antibody Technique; Humans; Immunology; Immunosuppression; Internal Medicine; L1 protein; MCF-7 Cells; Medical Microbiology; Mice; Mice, Nude; Neoplasm Transplantation; PD-1 protein; PD-L1 protein; Pharmacology/Toxicology; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcription; Tumors; Vaccine; HBXIP; transcription activation; PD-L1; protein acetylation; breast cancer
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00631-6

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.