Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells
In this study, we utilized an in vitro model consisting of human malignant melanoma as well as non-tumorigenic immortalized keratinocyte cells with the aim of characterizing the therapeutic effectiveness of the clinical epigenetic drug Tazemetostat alone or in combination with various isothiocyanate...
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/5/2745 |
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| author | Ioannis Anestopoulos Ioannis Paraskevaidis Sotiris Kyriakou Lambrini E. Giova Dimitrios T. Trafalis Sotiris Botaitis Rodrigo Franco Aglaia Pappa Mihalis I. Panayiotidis |
| author_facet | Ioannis Anestopoulos Ioannis Paraskevaidis Sotiris Kyriakou Lambrini E. Giova Dimitrios T. Trafalis Sotiris Botaitis Rodrigo Franco Aglaia Pappa Mihalis I. Panayiotidis |
| author_sort | Ioannis Anestopoulos |
| collection | DOAJ |
| description | In this study, we utilized an in vitro model consisting of human malignant melanoma as well as non-tumorigenic immortalized keratinocyte cells with the aim of characterizing the therapeutic effectiveness of the clinical epigenetic drug Tazemetostat alone or in combination with various isothiocyanates. In doing so, we assessed markers of cell viability, apoptotic induction, and expression levels of key proteins capable of mediating the therapeutic response. Our data indicated, for the first time, that Tazemetostat caused a significant decrease in viability levels of malignant melanoma cells in a dose- and time-dependent manner via the induction of apoptosis, while non-malignant keratinocytes were more resistant. Moreover, combinatorial treatment protocols caused a further decrease in cell viability, together with higher apoptotic rates. In addition, a significant reduction in the Polycomb Repressive Complex 2 (PRC2) members [e.g., Enhancer of Zeste Homologue 2 (EZH2), Embryonic Ectoderm Development (EED), and suppressor of zeste 12 (SUZ12)] and tri-methylating lysine 27 at Histone 3 (H3K27me3) protein expression levels was observed, at least partially, under specific combinatorial exposure conditions. Reactivation of major apoptotic gene targets was determined at much higher levels in combinatorial treatment protocols than Tazemetostat alone, known to be involved in the induction of intrinsic and extrinsic apoptosis. Overall, we developed an optimized experimental therapeutic platform aiming to ensure the therapeutic effectiveness of Tazemetostat in malignant melanoma while at the same time minimizing toxicity against neighboring non-tumorigenic keratinocyte cells. |
| first_indexed | 2024-04-25T00:29:31Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:29:31Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e8e1e020d2b84d4e8491814b20a58b7e2024-03-12T16:46:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01255274510.3390/ijms25052745Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma CellsIoannis Anestopoulos0Ioannis Paraskevaidis1Sotiris Kyriakou2Lambrini E. Giova3Dimitrios T. Trafalis4Sotiris Botaitis5Rodrigo Franco6Aglaia Pappa7Mihalis I. Panayiotidis8Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, CyprusDepartment of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, CyprusDepartment of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, CyprusDepartment of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, CyprusLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Surgery, School of Medicine, University Hospital, Democritus University of Thrace, 68100 Alexandroupolis, GreeceSchool of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USADepartment of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, GreeceDepartment of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, CyprusIn this study, we utilized an in vitro model consisting of human malignant melanoma as well as non-tumorigenic immortalized keratinocyte cells with the aim of characterizing the therapeutic effectiveness of the clinical epigenetic drug Tazemetostat alone or in combination with various isothiocyanates. In doing so, we assessed markers of cell viability, apoptotic induction, and expression levels of key proteins capable of mediating the therapeutic response. Our data indicated, for the first time, that Tazemetostat caused a significant decrease in viability levels of malignant melanoma cells in a dose- and time-dependent manner via the induction of apoptosis, while non-malignant keratinocytes were more resistant. Moreover, combinatorial treatment protocols caused a further decrease in cell viability, together with higher apoptotic rates. In addition, a significant reduction in the Polycomb Repressive Complex 2 (PRC2) members [e.g., Enhancer of Zeste Homologue 2 (EZH2), Embryonic Ectoderm Development (EED), and suppressor of zeste 12 (SUZ12)] and tri-methylating lysine 27 at Histone 3 (H3K27me3) protein expression levels was observed, at least partially, under specific combinatorial exposure conditions. Reactivation of major apoptotic gene targets was determined at much higher levels in combinatorial treatment protocols than Tazemetostat alone, known to be involved in the induction of intrinsic and extrinsic apoptosis. Overall, we developed an optimized experimental therapeutic platform aiming to ensure the therapeutic effectiveness of Tazemetostat in malignant melanoma while at the same time minimizing toxicity against neighboring non-tumorigenic keratinocyte cells.https://www.mdpi.com/1422-0067/25/5/2745melanomaTazemetostatisothiocyanatesepigeneticstherapeuticsapoptosis |
| spellingShingle | Ioannis Anestopoulos Ioannis Paraskevaidis Sotiris Kyriakou Lambrini E. Giova Dimitrios T. Trafalis Sotiris Botaitis Rodrigo Franco Aglaia Pappa Mihalis I. Panayiotidis Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells International Journal of Molecular Sciences melanoma Tazemetostat isothiocyanates epigenetics therapeutics apoptosis |
| title | Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells |
| title_full | Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells |
| title_fullStr | Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells |
| title_full_unstemmed | Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells |
| title_short | Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells |
| title_sort | isothiocyanates potentiate tazemetostat induced apoptosis by modulating the expression of apoptotic genes members of polycomb repressive complex 2 and levels of tri methylating lysine 27 at histone 3 in human malignant melanoma cells |
| topic | melanoma Tazemetostat isothiocyanates epigenetics therapeutics apoptosis |
| url | https://www.mdpi.com/1422-0067/25/5/2745 |
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