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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Bibliographic Details
Published in:JCI insight 2022-10, Vol.7 (19)
Main Authors: 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
Format: Article
Language:English
Subjects:
Cancer and Oncology
Cancer och onkologi
Cell biology
Clinical Medicine
Klinisk medicin
Medical and Health Sciences
Medicin och hälsovetenskap
Oncology
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.156577