title: DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR.
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.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Goran
authors.initials: G
authors.lastname: Micevic
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Chemistry, Yale University, New Haven, CT 06510, USA.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Muthusamy
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: William
authors.initials: W
authors.lastname: Damsky
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Theodosakis
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Meeth
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Wingrove
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Santhanakrishnan
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: marcus.bosenberg@yale.edu.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism; D009368:Neoplasm Transplantation; D016016:Proportional Hazards Models; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012878:Skin Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden; D000097584:DNA Methyltransferase 3B
chemical_list: D002352:Carrier Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000076225:Mechanistic Target of Rapamycin Complex 2; D035683:MicroRNAs; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D000097584:DNA Methyltransferase 3B; C000602251:MIRN196 microRNA, mouse; C525637:rictor protein, mouse