title: MicroRNAs miR-199a-5p and -3p target the Brm subunit of SWI/SNF to generate a double-negative feedback loop in a variety of human cancers.
abstract: The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3'-untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or downregulated in a variety of tumors.
authors.affiliation: Division of Host-Parasite Interaction, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Sakurai
authors.forename: Chihiro
authors.initials: C
authors.lastname: Furukawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Haraguchi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shiogama
authors.forename: Takanobu
authors.initials: T
authors.lastname: Tagawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Fujita
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Ueno
authors.forename: Aya
authors.initials: A
authors.lastname: Ogata
authors.forename: Mai
authors.initials: M
authors.lastname: Ito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Hideo
authors.initials: H
authors.lastname: Iba
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D025461:Feedback, Physiological / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D035683:MicroRNAs; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C531408:mirn199 microRNA, human