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DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype

Sanna, Adriana LU orcid ; Phung, Bengt LU ; Mitra, Shamik LU ; Lauss, Martin LU ; Choi, Jiyeon ; Zhang, Tongwu ; Njauw, Ching-Ni Jenny ; Cordero, Eugenia LU ; Harbst, Katja LU orcid and Rosengren, Frida LU , et al. (2022) In JCI Insight 7(19).
Abstract

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, MITF and 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 two distinct... (More)

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, MITF and 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 two distinct subtypes. Examining mRNA levels of neural crest associated genes we found that one 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 confirmed 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
7
issue
19
article number
e156577
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85139571437
  • pmid:36040798
ISSN
2379-3708
DOI
10.1172/jci.insight.156577
language
English
LU publication?
yes
id
f02b5045-f4be-4dfb-aee5-55cacc486133
date added to LUP
2022-09-07 16:20:02
date last changed
2025-03-07 21:26:47
@article{f02b5045-f4be-4dfb-aee5-55cacc486133,
  abstract     = {{<p>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, MITF and 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 two distinct subtypes. Examining mRNA levels of neural crest associated genes we found that one 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 confirmed these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.</p>}},
  author       = {{Sanna, Adriana and Phung, Bengt and Mitra, Shamik and Lauss, Martin and Choi, Jiyeon and Zhang, Tongwu and Njauw, Ching-Ni Jenny and Cordero, Eugenia and Harbst, Katja and Rosengren, Frida and Cabrita, Rita and Johansson, Iva and Isaksson, Karolin and Ingvar, Christian and Carneiro, Ana and Brown, Kevin and Tsao, Hensin and Andersson, My and Pietras, Kristian and Jönsson, Göran}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.156577}},
  doi          = {{10.1172/jci.insight.156577}},
  volume       = {{7}},
  year         = {{2022}},
}