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TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Yinghui Shen1, Lu Liu1, Mengyuan Wang1

  • 1Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Cancers
|June 2, 2021
PubMed

Insights

TET2 epigenetic regulation suppresses PD-L1 expression in breast cancer. TET2 recruits HDACs to the PD-L1 promoter, reducing immune evasion and enhancing anti-tumor immunity.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Immunology

Background:

  • Programmed cell death protein 1 (PD-1)/PD-L1 pathway is crucial for tumor immune evasion.
  • Aberrant PD-L1 expression in breast cancer is linked to poor prognosis.
  • Epigenetic mechanisms regulating PD-L1 in breast cancer are not fully understood.

Purpose of the Study:

  • To investigate the role of TET2 in regulating PD-L1 gene expression in breast cancer.
  • To elucidate the epigenetic mechanism by which TET2 influences PD-L1 transcription.

Main Methods:

  • Quantitative reverse transcription PCR (RT-qPCR) and Western blotting.
  • Chromatin immunoprecipitation (ChIP) assay and methylation-based DNA immunoprecipitation (MeDIP/hMeDIP)-qPCR.
  • Analysis of CCLE and TCGA datasets for gene expression correlation.

Main Results:

  • TET2 depletion increased PD-L1 expression in MCF7 cells; TET2 overexpression decreased it in MDA-MB-231 cells.
  • TET2 recruits histone deacetylases (HDACs) to the PD-L1 promoter, forming repressive chromatin.
  • HDAC inhibition upregulated PD-L1 in WT but not TET2-deficient cells, suggesting a catalytic activity-independent role for TET2.
  • A negative correlation between TET2 and PD-L1 expression was observed in breast cancer data.

Conclusions:

  • TET2 functions as a transcriptional repressor of PD-L1 in breast cancer.
  • This regulation occurs via recruitment of HDACs, independent of DNA demethylation.
  • Identifies a novel epigenetic mechanism linking TET2 to anti-tumor immunity in breast cancer.
Keywords:
HDACPD-L1TET2breast cancerepigenetic regulation

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