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Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
Maria Anele Romeo1, Maria Saveria Gilardini Montani1, Roberta Santarelli1
1Department of Experimental Medicine, "Sapienza" University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
Discover Oncology
|August 21, 2023
Summary
Valproic acid (VPA), an HDAC inhibitor, increases PD-L1 on pancreatic cancer cells by enhancing gene transcription and protein acetylation. Combining VPA with a BRD4 inhibitor like JQ-1 may improve cancer treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Programmed death-ligand 1 (PD-L1) is crucial for cancer cells to evade immune surveillance.
- Epigenetic modifications, including acetylation, influence PD-L1 expression and localization.
- Histone deacetylase (HDAC) inhibitors are investigated for their potential in cancer therapy.
Purpose of the Study:
- To investigate the effect of VPA, a class I/IIa HDAC inhibitor, on PD-L1 expression in pancreatic cancer.
- To elucidate the molecular mechanisms underlying VPA-induced PD-L1 upregulation.
- To evaluate the potential of combining VPA with a BRD4 inhibitor for enhanced anti-cancer effects.
Main Methods:
- Treatment of pancreatic cancer cells with VPA and JQ-1 (BRD4 inhibitor).
- Analysis of PD-L1 surface expression and gene transcription.
- Assessment of histone and PD-L1 protein acetylation.
- Investigation of TRAPPC4 interaction and PD-L1 recycling.
- Evaluation of combined treatment cytotoxicity.
Main Results:
- VPA significantly upregulated surface PD-L1 expression on pancreatic cancer cells.
- Increased PD-L1 transcription correlated with histone acetylation of the PD-L1 gene.
- PD-L1 protein acetylation enhanced its interaction with TRAPPC4, promoting cell membrane recycling.
- JQ-1 counteracted VPA-induced PD-L1 transcription and surface expression.
- Combination therapy demonstrated increased VPA cytotoxicity.
Conclusions:
- VPA promotes PD-L1 surface expression in pancreatic cancer via epigenetic mechanisms, including histone and protein acetylation.
- Targeting BRD4 in combination with VPA may represent a promising strategy to overcome immune evasion and enhance therapeutic efficacy.
- VPA's effects are specific to PD-L1 and do not affect PD-L2 or macrophage PD-L1 expression.
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