Journal
CELL REPORTS
Volume 14, Issue 9, Pages 2180-2192Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.02.010
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Funding
- Yale Cancer Center
- Hervey Family Fund
- Sokoloff Family-Melanoma Research Alliance Team Science Award
- Yale SPORE in Skin Cancer [P50 CA121974]
- Joanna M. Nicolay Melanoma Foundation
- Yale MSTP NIH [T32 GM007205]
- NRSA [F30 CA19608901]
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DNA methyltransferase DNMT3B is frequently overexpressed in tumor cells and plays important roles during the formation and progression of several cancer types. However, the specific signaling pathways controlled by DNMT3B in cancers, including melanoma, are poorly understood. Here, we report that DNMT3B plays a pro-tumorigenic role in human melanoma and that DNMT3B loss dramatically suppresses melanoma formation in the Braf/Pten mouse melanoma model. Loss of DNMT3B results in hypomethylation of the miR-196b promoter and increased miR-196b expression, which directly targets the mTORC2 component Rictor. Loss of RICTOR in turn prevents mTORC2 activation, which is critical for melanoma formation and growth. These findings establish Dnmt3b as a regulator of melanoma formation through its effect on mTORC2 signaling. Based on these results, DNMT3B is a potential therapeutic target in melanoma.
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