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.
Highlights
Chromatin-modifying enzymes are subject to alterations in a diverse range of developmental disorders and cancers
Given the known oncogenic function of H3K9 histone methyltransferases (HMTs) in melanoma, we hypothesized that H3.3K9M would suppress melanoma formation
Using cBioPortal (Cerami et al, 2012; Gao et al, 2013), we identified a single case of melanoma with a K9M mutation in histone 3, underscoring the importance of H3K9me3 in human melanoma
Summary
Chromatin-modifying enzymes are subject to alterations in a diverse range of developmental disorders and cancers. PRC2 components are subject to gain and loss of Histone Methyltransferase Function in Melanoma function in a wide set of set of human cancers, including follicular and diffuse large B-cell lymphoma (Morin et al, 2010; McCabe et al, 2012), myelodysplastic syndromes (Nikoloski et al, 2010; Score et al, 2012), malignant peripheral nerve sheath tumors (De Raedt et al, 2014; Lee et al, 2014), and melanoma (Souroullas et al, 2016). These genetic studies demonstrate that the function of PRC2 as a tumor suppressor or oncogene is context dependent
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