Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness
Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The <i>TP53</i> gene, the guardian of the genome, which is altered in more than 50% of human ca...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/20/5231 |
| _version_ | 1797515076498882560 |
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| author | Ana Tadijan Francesca Precazzini Nikolina Hanžić Martina Radić Nicolò Gavioli Ignacija Vlašić Petar Ozretić Lia Pinto Lidija Škreblin Giulia Barban Neda Slade Yari Ciribilli |
| author_facet | Ana Tadijan Francesca Precazzini Nikolina Hanžić Martina Radić Nicolò Gavioli Ignacija Vlašić Petar Ozretić Lia Pinto Lidija Škreblin Giulia Barban Neda Slade Yari Ciribilli |
| author_sort | Ana Tadijan |
| collection | DOAJ |
| description | Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The <i>TP53</i> gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different <i>TP53</i> and <i>BRAF</i> status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness. |
| first_indexed | 2024-03-10T06:40:29Z |
| format | Article |
| id | doaj.art-75464113eef1450fbc08620121b9179d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:40:29Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-75464113eef1450fbc08620121b9179d2023-11-22T17:42:25ZengMDPI AGCancers2072-66942021-10-011320523110.3390/cancers13205231Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma AggressivenessAna Tadijan0Francesca Precazzini1Nikolina Hanžić2Martina Radić3Nicolò Gavioli4Ignacija Vlašić5Petar Ozretić6Lia Pinto7Lidija Škreblin8Giulia Barban9Neda Slade10Yari Ciribilli11Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, ItalyLaboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, ItalyLaboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, ItalyLaboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, ItalyLaboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaLaboratory of Molecular Cancer Genetics, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, 38123 Povo, TN, ItalyCutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The <i>TP53</i> gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different <i>TP53</i> and <i>BRAF</i> status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness.https://www.mdpi.com/2072-6694/13/20/5231melanomap53p73Δ160p53isoformstargeted therapy |
| spellingShingle | Ana Tadijan Francesca Precazzini Nikolina Hanžić Martina Radić Nicolò Gavioli Ignacija Vlašić Petar Ozretić Lia Pinto Lidija Škreblin Giulia Barban Neda Slade Yari Ciribilli Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness Cancers melanoma p53 p73 Δ160p53 isoforms targeted therapy |
| title | Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness |
| title_full | Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness |
| title_fullStr | Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness |
| title_full_unstemmed | Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness |
| title_short | Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness |
| title_sort | altered expression of shorter p53 family isoforms can impact melanoma aggressiveness |
| topic | melanoma p53 p73 Δ160p53 isoforms targeted therapy |
| url | https://www.mdpi.com/2072-6694/13/20/5231 |
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