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, Béguelin 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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