ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1
Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of aut...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.721624/full |
| _version_ | 1818607850981687296 |
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| author | Živa Frangež Deborah Gérard Zhaoyue He Marios Gavriil Yuniel Fernández-Marrero Yuniel Fernández-Marrero S. Morteza Seyed Jafari Robert E. Hunger Philippe Lucarelli Shida Yousefi Thomas Sauter Lasse Sinkkonen Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon |
| author_facet | Živa Frangež Deborah Gérard Zhaoyue He Marios Gavriil Yuniel Fernández-Marrero Yuniel Fernández-Marrero S. Morteza Seyed Jafari Robert E. Hunger Philippe Lucarelli Shida Yousefi Thomas Sauter Lasse Sinkkonen Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon |
| author_sort | Živa Frangež |
| collection | DOAJ |
| description | Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes. |
| first_indexed | 2024-12-16T14:33:19Z |
| format | Article |
| id | doaj.art-92f2f53d26a24de8bac3faed30cc5478 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-16T14:33:19Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-92f2f53d26a24de8bac3faed30cc54782022-12-21T22:28:10ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-08-011110.3389/fonc.2021.721624721624ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1Živa Frangež0Deborah Gérard1Zhaoyue He2Marios Gavriil3Yuniel Fernández-Marrero4Yuniel Fernández-Marrero5S. Morteza Seyed Jafari6Robert E. Hunger7Philippe Lucarelli8Shida Yousefi9Thomas Sauter10Lasse Sinkkonen11Hans-Uwe Simon12Hans-Uwe Simon13Hans-Uwe Simon14Hans-Uwe Simon15Institute of Pharmacology, University of Bern, Bern, SwitzerlandDepartment of Life Sciences and Medicine, University of Luxembourg, Belvaux, LuxembourgInstitute of Pharmacology, University of Bern, Bern, SwitzerlandDepartment of Life Sciences and Medicine, University of Luxembourg, Belvaux, LuxembourgInstitute of Pharmacology, University of Bern, Bern, SwitzerlandBiological Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Science Centre, Toronto, ON, CanadaDepartment of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandDepartment of Life Sciences and Medicine, University of Luxembourg, Belvaux, LuxembourgInstitute of Pharmacology, University of Bern, Bern, SwitzerlandDepartment of Life Sciences and Medicine, University of Luxembourg, Belvaux, LuxembourgDepartment of Life Sciences and Medicine, University of Luxembourg, Belvaux, LuxembourgInstitute of Pharmacology, University of Bern, Bern, SwitzerlandInstitute of Biochemistry, Medical School Brandenburg, Neuruppin, GermanyDepartment of Clinical Immunology and Allergology, Sechenov University, Moscow, RussiaLaboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, RussiaAutophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes.https://www.frontiersin.org/articles/10.3389/fonc.2021.721624/fullautophagyATG5ATG7melanomaNRF1transcription factor |
| spellingShingle | Živa Frangež Deborah Gérard Zhaoyue He Marios Gavriil Yuniel Fernández-Marrero Yuniel Fernández-Marrero S. Morteza Seyed Jafari Robert E. Hunger Philippe Lucarelli Shida Yousefi Thomas Sauter Lasse Sinkkonen Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon Hans-Uwe Simon ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 Frontiers in Oncology autophagy ATG5 ATG7 melanoma NRF1 transcription factor |
| title | ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 |
| title_full | ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 |
| title_fullStr | ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 |
| title_full_unstemmed | ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 |
| title_short | ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1 |
| title_sort | atg5 and atg7 expression levels are reduced in cutaneous melanoma and regulated by nrf1 |
| topic | autophagy ATG5 ATG7 melanoma NRF1 transcription factor |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.721624/full |
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