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

Acta Pharmacol Sin. 2022 Feb;43(2):429-445. doi: 10.1038/s41401-021-00631-6. Epub 2021 Apr 6.

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.

Keywords: HBXIP; PD-L1; breast cancer; protein acetylation; transcription activation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • B7-H1 Antigen / metabolism*
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / 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

Substances

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