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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
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.
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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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