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Histone 3 Methyltransferases Alter Melanoma Initiation and Progression Through Discrete Mechanisms.

TitleHistone 3 Methyltransferases Alter Melanoma Initiation and Progression Through Discrete Mechanisms.
Publication TypeJournal Article
Year of Publication2022
AuthorsDiNapoli SE, Martinez-McFaline R, Shen H, Doane AS, Perez AR, Verma A, Simon A, Nelson I, Balgobin CA, Bourque CT, Yao J, Raman R, B├ęguelin W, Zippin JH, Elemento O, Melnick AM, Houvras Y
JournalFront Cell Dev Biol
Volume10
Pagination814216
Date Published2022
ISSN2296-634X
Abstract

Perturbations to the epigenome are known drivers of tumorigenesis. In melanoma, alterations in histone methyltransferases that catalyze methylation at histone 3 lysine 9 and histone 3 lysine 27-two sites of critical post-translational modification-have been reported. To study the function of these methyltransferases in melanoma, we engineered melanocytes to express histone 3 lysine-to-methionine mutations at lysine 9 and lysine 27, which are known to inhibit the activity of histone methyltransferases, in a zebrafish melanoma model. Using this system, we found that loss of histone 3 lysine 9 methylation dramatically suppressed melanoma formation and that inhibition of histone 3 lysine 9 methyltransferases in human melanoma cells increased innate immune response signatures. In contrast, loss of histone 3 lysine 27 methylation significantly accelerated melanoma formation. We identified FOXD1 as a top target of PRC2 that is silenced in melanocytes and found that aberrant overexpression of FOXD1 accelerated melanoma onset. Collectively, these data demonstrate how histone 3 lysine-to-methionine mutations can be used to uncover critical roles for methyltransferases.

DOI10.3389/fcell.2022.814216
Alternate JournalFront Cell Dev Biol
PubMed ID35223844
PubMed Central IDPMC8866878

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