title: Restoration of miR-101 suppresses lung tumorigenesis through inhibition of DNMT3a-dependent DNA methylation.
abstract: The deregulation of miR-101 and DNMT3a has been implicated in the pathogenesis of multiple tumor types, but whether and how miR-101 silencing and DNMT3a overexpression contribute to lung tumorigenesis remain elusive. Here we show that miR-101 downregulation associates with DNMT3a overexpression in lung cancer cell lines and patient tissues. Ectopic miR-101 expression remarkably abrogated the DNMT3a 3'-UTR luciferase activity corresponding to the miR-101 binding site and caused an attenuated expression of endogenous DNMT3a, which led to a reduction of global DNA methylation and the re-expression of tumor suppressor CDH1 via its promoter DNA hypomethylation. Functionally, restoration of miR-101 expression suppressed lung cancer cell clonability and migration, which recapitulated the DNMT3a knockdown effects. Interestingly, miR-101 synergized with decitabine to downregulate DNMT3a and to reduce DNA methylation. Importantly, ectopic miR-101 expression was sufficient to trigger in vivo lung tumor regression and the blockage of metastasis. Consistent with these phenotypes, examination of xenograft tumors disclosed an increase of miR-101, a decrease of DNMT3a and the subsequent DNA demethylation. These findings support that the loss or suppression of miR-101 function accelerates lung tumorigenesis through DNMT3a-dependent DNA methylation, and suggest that miR-101-DNMT3a axis may have therapeutic value in treating refractory lung cancer.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yan
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shen
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pang
authors.affiliation: Division of Epidemiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: D
authors.initials: D
authors.lastname: Xie
authors.affiliation: Division of Epidemiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: B
authors.initials: B
authors.lastname: Deng
authors.affiliation: Division of Medical Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Molina
authors.affiliation: Division of Epidemiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A