Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma
Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HD...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/15/2380 |
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| author | Maša Zrimšek Hana Kuchaříková Kristina Draganić Pavlína Dobrovolná Verena Heiss Spornberger Lisa Winkelmayer Melanie R. Hassler Gabriela Lochmanová Zbyněk Zdráhal Gerda Egger |
| author_facet | Maša Zrimšek Hana Kuchaříková Kristina Draganić Pavlína Dobrovolná Verena Heiss Spornberger Lisa Winkelmayer Melanie R. Hassler Gabriela Lochmanová Zbyněk Zdráhal Gerda Egger |
| author_sort | Maša Zrimšek |
| collection | DOAJ |
| description | Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of <i>Hdac1</i>. Changes in overall protein expression as well as histone and protein acetylation were measured following <i>Hdac1</i> deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies. |
| first_indexed | 2024-03-09T05:31:48Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T05:31:48Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-efd61c7324fb49a5b4b37032ea4eba8d2023-12-03T12:32:27ZengMDPI AGCells2073-44092022-08-011115238010.3390/cells11152380Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell LymphomaMaša Zrimšek0Hana Kuchaříková1Kristina Draganić2Pavlína Dobrovolná3Verena Heiss Spornberger4Lisa Winkelmayer5Melanie R. Hassler6Gabriela Lochmanová7Zbyněk Zdráhal8Gerda Egger9Department of Pathology, Medical University of Vienna, 1090 Vienna, AustriaCentral European Institute of Technology, Masaryk University, 625 00 Brno, Czech RepublicDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaCentral European Institute of Technology, Masaryk University, 625 00 Brno, Czech RepublicDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaCentral European Institute of Technology, Masaryk University, 625 00 Brno, Czech RepublicCentral European Institute of Technology, Masaryk University, 625 00 Brno, Czech RepublicDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaHistone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of <i>Hdac1</i>. Changes in overall protein expression as well as histone and protein acetylation were measured following <i>Hdac1</i> deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies.https://www.mdpi.com/2073-4409/11/15/2380histone deacetylaseshistone deacetylase inhibitorsSAHAvorinostatMS-275entinostat |
| spellingShingle | Maša Zrimšek Hana Kuchaříková Kristina Draganić Pavlína Dobrovolná Verena Heiss Spornberger Lisa Winkelmayer Melanie R. Hassler Gabriela Lochmanová Zbyněk Zdráhal Gerda Egger Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma Cells histone deacetylases histone deacetylase inhibitors SAHA vorinostat MS-275 entinostat |
| title | Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma |
| title_full | Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma |
| title_fullStr | Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma |
| title_full_unstemmed | Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma |
| title_short | Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma |
| title_sort | quantitative acetylomics uncover acetylation mediated pathway changes following histone deacetylase inhibition in anaplastic large cell lymphoma |
| topic | histone deacetylases histone deacetylase inhibitors SAHA vorinostat MS-275 entinostat |
| url | https://www.mdpi.com/2073-4409/11/15/2380 |
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