title: A miR-34a-SIRT6 axis in the squamous cell differentiation network.
abstract: Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA-34a (miR-34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR-34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild-type p53 expression. In normal HKCs, the pro-differentiation effects of increased p53 activity or UVB exposure are miR-34a-dependent, and increased miR-34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR-34a function, is a direct target of this miRNA in HKCs, and SIRT6 down-modulation is sufficient to reproduce the miR-34a pro-differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR-34a in normal keratinocytes and keratinocyte-derived tumours.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. karine.lefort@unil.ch
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.forename: Yang
authors.initials: Y
authors.lastname: Brooks
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.forename: Muriel
authors.initials: M
authors.lastname: Cario-André
authors.forename: Valérie
authors.initials: V
authors.lastname: Calpini
authors.forename: Juan
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.forename: Andrea
authors.initials: A
authors.lastname: Albinger-Hegyi
authors.forename: Wolfram
authors.initials: W
authors.lastname: Hoetzenecker
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kolfschoten
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Dotto
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology* / Q000528:radiation effects; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D017931:DNA Primers; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; C516592:SIRT6 protein, human; D037761:Sirtuins