Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors

The American Journal of Pathology
Maximilian GassenmaierMartin Röcken

Abstract

Aberrant DNA methylation is an epigenetic hallmark of melanoma and hypomethylating drugs with immunomodulatory activity are currently investigated in clinical trials. DNA methyltransferase 1 (DNMT1) is the major maintenance methyltransferase but its expression in melanocytic tumors is unknown. We analyzed DNMT1 expression in primary melanocytes, melanoma cell lines and 83 melanocytic tumors and explored its association with proliferation, mutational status and response to BRAF and MEK inhibition. We found that DNMT1 expression increased incrementally from nevi (mean fluorescence intensity (MFI) 48.1, interquartile range (IQR) 41.7 - 59.6) to primary melanomas (MFI 68.8, IQR 58.4 - 77.0) and metastatic melanomas (MFI 87.5, IQR 77.1 - 114.5; P < 0.001). DNMT1 expression correlated with Ki67 expression (Spearman correlation 0.483; P < 0.001) and was independent of the BRAF mutational status (P = 0.55). In BRAF mutant melanoma, DNMT1 was downregulated during response to BRAF and MEK inhibition and was again upregulated upon drug resistance in vitro and in vivo. Degradation of DNMT1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid decreased cell viability in BRAF inhibitor sensitive and resistant cell lines. Our ...Continue Reading

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Citations

Jun 14, 2021·Journal of Molecular Biology·Alessio ButeraIvano Amelio

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