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Expression of DNA Methyltransferase 1 Is a Hallmark of Melanoma, Correlating with Proliferation and Response to B-Raf and Mitogen-Activated Protein Kinase Inhibition in Melanocytic Tumors
- Source :
- The American journal of pathology. 190(10)
- Publication Year :
- 2020
-
Abstract
- Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy.
- Subjects :
- 0301 basic medicine
Proto-Oncogene Proteins B-raf
Methyltransferase
Skin Neoplasms
DNA methyltransferase
Pathology and Forensic Medicine
03 medical and health sciences
0302 clinical medicine
Interquartile range
Cell Line, Tumor
medicine
Humans
Epigenetics
neoplasms
Melanoma
Protein Kinase Inhibitors
Cell Proliferation
Mitogen-Activated Protein Kinase Kinases
Vorinostat
biology
business.industry
DNA
medicine.disease
Histone Deacetylase Inhibitors
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
DNMT1
Cancer research
biology.protein
Melanocytes
Mitogen-Activated Protein Kinases
business
Subjects
Details
- ISSN :
- 15252191
- Volume :
- 190
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- The American journal of pathology
- Accession number :
- edsair.doi.dedup.....45a1f34666fa556fed5cff5877b830b1