AUTHOR=DiNapoli Sara E. , Martinez-McFaline Raúl , Shen Hao , Doane Ashley S. , Perez Alexendar R. , Verma Akanksha , Simon Amanda , Nelson Isabel , Balgobin Courtney A. , Bourque Caitlin T. , Yao Jun , Raman Renuka , Béguelin Wendy , Zippin Jonathan H. , Elemento Olivier , Melnick Ari M. , Houvras Yariv TITLE=Histone 3 Methyltransferases Alter Melanoma Initiation and Progression Through Discrete Mechanisms JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=10 YEAR=2022 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.814216 DOI=10.3389/fcell.2022.814216 ISSN=2296-634X 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.