5-Hydroxymethylcytosine loss occurs during melanoma progression and drives tumor growth.
Major finding: 5-Hydroxymethylcytosine loss occurs during melanoma progression and drives tumor growth.
Mechanism: IDH2, TET1, TET2, and TET3 expression is downregulated in melanoma compared with nevi.
Impact: 5-Hydroxymethylcytosine levels may have diagnostic and prognostic value in melanoma.
Histologic similarities between benign and malignant melanocytic lesions can hinder diagnosis and efforts to predict clinical outcome. Cancerous cells can frequently be distinguished from benign cells by genome-wide abnormalities in epigenetic marks, such as 5-hydroxymethylcytosine (5-hmC), which has been shown to be globally reduced in tumor cells. This finding, together with the observation that gain-of-function isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations that block the conversion of 5-methylcytosine to 5-hmC occur in 10% of melanomas, led Lian and colleagues to hypothesize that 5-hmC levels might distinguish malignant melanoma from benign melanocytic nevi. Indeed, mature melanocytes and benign nevi had high nuclear levels of 5-hmC, whereas 5-hmC was partially or completely lost in most primary or metastatic melanomas. Furthermore, 5-hmC loss was correlated with a higher tumor stage, was associated with a worse prognosis, and was enriched at genes associated with melanogenesis and cancer-related pathways, suggesting that a progressive change in the 5-hmC landscape contributes to tumor formation. To determine how 5-hmC depletion might occur, the authors evaluated the expression levels of the ten-eleven translocation (TET) family of DNA hydroxylases that directly generate 5-hmC as well as IDH1 and IDH2, which normally generate the key cofactor required by TET enzymes. Compared with nevi, IDH2 and all 3 TET genes (TET1-3) were significantly downregulated in melanoma patient samples, implicating downregulation of enzymes required for the generation of 5-hmC in melanomagenesis. Consistent with this possibility, IDH2 overexpression in a zebrafish melanoma model increased 5-hmC levels and delayed tumor formation, and TET2 overexpression in human melanoma cells reestablished the 5-hmC landscape and slowed xenograft tumor growth. Collectively, these findings suggest that 5-hmC loss drives melanoma progression and that restoration of genome-wide 5-hmC levels may suppress melanoma growth.