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Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1

PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/II...

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Autores principales: Romeo, Maria Anele, Gilardini Montani, Maria Saveria, Santarelli, Roberta, Benedetti, Rossella, Arena, Andrea, Cirone, Mara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442048/
https://www.ncbi.nlm.nih.gov/pubmed/37603071
http://dx.doi.org/10.1007/s12672-023-00766-4
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author Romeo, Maria Anele
Gilardini Montani, Maria Saveria
Santarelli, Roberta
Benedetti, Rossella
Arena, Andrea
Cirone, Mara
author_facet Romeo, Maria Anele
Gilardini Montani, Maria Saveria
Santarelli, Roberta
Benedetti, Rossella
Arena, Andrea
Cirone, Mara
author_sort Romeo, Maria Anele
collection PubMed
description PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-023-00766-4.
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spelling pubmed-104420482023-08-22 Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1 Romeo, Maria Anele Gilardini Montani, Maria Saveria Santarelli, Roberta Benedetti, Rossella Arena, Andrea Cirone, Mara Discov Oncol Research PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-023-00766-4. Springer US 2023-08-21 /pmc/articles/PMC10442048/ /pubmed/37603071 http://dx.doi.org/10.1007/s12672-023-00766-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Romeo, Maria Anele
Gilardini Montani, Maria Saveria
Santarelli, Roberta
Benedetti, Rossella
Arena, Andrea
Cirone, Mara
Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title_full Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title_fullStr Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title_full_unstemmed Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title_short Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
title_sort acetylation increases expression, interaction with trappc4 and surface localization of pd-l1
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442048/
https://www.ncbi.nlm.nih.gov/pubmed/37603071
http://dx.doi.org/10.1007/s12672-023-00766-4
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