DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR

Cell Rep. 2016 Mar 8;14(9):2180-2192. doi: 10.1016/j.celrep.2016.02.010. Epub 2016 Feb 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferases / physiology*
  • DNA Methylation
  • DNA Methyltransferase 3B
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Melanoma, Experimental / enzymology*
  • Melanoma, Experimental / mortality
  • Melanoma, Experimental / pathology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / genetics
  • Multiprotein Complexes / metabolism
  • Neoplasm Transplantation
  • Proportional Hazards Models
  • RNA Interference
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Burden

Substances

  • Carrier Proteins
  • MIRN196 microRNA, mouse
  • MicroRNAs
  • Multiprotein Complexes
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • DNA (Cytosine-5-)-Methyltransferases
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases