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DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype
Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675437/ https://www.ncbi.nlm.nih.gov/pubmed/36040798 http://dx.doi.org/10.1172/jci.insight.156577 |
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author | Sanna, Adriana Phung, Bengt Mitra, Shamik Lauss, Martin Choi, Jiyeon Zhang, Tongwu Njauw, Ching-Ni Cordero, Eugenia Harbst, Katja Rosengren, Frida Cabrita, Rita Johansson, Iva Isaksson, Karolin Ingvar, Christian Carneiro, Ana Brown, Kevin Tsao, Hensin Andersson, My Pietras, Kristian Jönsson, Göran |
author_facet | Sanna, Adriana Phung, Bengt Mitra, Shamik Lauss, Martin Choi, Jiyeon Zhang, Tongwu Njauw, Ching-Ni Cordero, Eugenia Harbst, Katja Rosengren, Frida Cabrita, Rita Johansson, Iva Isaksson, Karolin Ingvar, Christian Carneiro, Ana Brown, Kevin Tsao, Hensin Andersson, My Pietras, Kristian Jönsson, Göran |
author_sort | Sanna, Adriana |
collection | PubMed |
description | Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest–associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states. |
format | Online Article Text |
id | pubmed-9675437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-96754372022-11-21 DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype Sanna, Adriana Phung, Bengt Mitra, Shamik Lauss, Martin Choi, Jiyeon Zhang, Tongwu Njauw, Ching-Ni Cordero, Eugenia Harbst, Katja Rosengren, Frida Cabrita, Rita Johansson, Iva Isaksson, Karolin Ingvar, Christian Carneiro, Ana Brown, Kevin Tsao, Hensin Andersson, My Pietras, Kristian Jönsson, Göran JCI Insight Research Article Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest–associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states. American Society for Clinical Investigation 2022-10-10 /pmc/articles/PMC9675437/ /pubmed/36040798 http://dx.doi.org/10.1172/jci.insight.156577 Text en © 2022 Sanna et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Sanna, Adriana Phung, Bengt Mitra, Shamik Lauss, Martin Choi, Jiyeon Zhang, Tongwu Njauw, Ching-Ni Cordero, Eugenia Harbst, Katja Rosengren, Frida Cabrita, Rita Johansson, Iva Isaksson, Karolin Ingvar, Christian Carneiro, Ana Brown, Kevin Tsao, Hensin Andersson, My Pietras, Kristian Jönsson, Göran DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title | DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title_full | DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title_fullStr | DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title_full_unstemmed | DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title_short | DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
title_sort | dna promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675437/ https://www.ncbi.nlm.nih.gov/pubmed/36040798 http://dx.doi.org/10.1172/jci.insight.156577 |
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