title: SNHG16 is regulated by the Wnt pathway in colorectal cancer and affects genes involved in lipid metabolism.
abstract: It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA-sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up-regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt-regulated transcription factors, including ASCL2, ETS2, and c-Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO-CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) "sponging" miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3'UTR of Stearoyl-CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down-regulated upon SNHG16 silencing. In conclusion, up-regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms.
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: liselotte.christensen@clin.au.dk.
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Christensen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: Kirsten_true@hotmail.com.
authors.forename: Kirsten
authors.initials: K
authors.lastname: True
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: mphamilt@bcm.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hamilton
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: morten.muhlig@clin.au.dk.
authors.forename: Morten M
authors.initials: MM
authors.lastname: Nielsen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. Electronic address: Nkerorema.Damas@bric.ku.dk.
authors.forename: Nkerorema D
authors.initials: ND
authors.lastname: Damas
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Denmark. Electronic address: ckd@mbg.au.dk.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Damgaard
authors.affiliation: Department of Genetic Medicine and Development, Functional Population Genomics and Genetics of Complex Traits Lab, University of Geneva Medical School, Geneva, Switzerland. Electronic address: Halit.Ongen@unige.ch.
authors.forename: Halit
authors.initials: H
authors.lastname: Ongen
authors.affiliation: Department of Genetic Medicine and Development, Functional Population Genomics and Genetics of Complex Traits Lab, University of Geneva Medical School, Geneva, Switzerland. Electronic address: Emmanouil.Dermitzakis@unige.ch.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Dermitzakis
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: bramsen@clin.au.dk.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Bramsen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: jakob.skou@clin.au.dk.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. Electronic address: anders.lund@bric.ku.dk.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Lund
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: vang@clin.au.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.affiliation: Department of Pathology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: katrine.stribolt@rm.dk.
authors.forename: Katrine
authors.initials: K
authors.lastname: Stribolt
authors.affiliation: Surgical Research Unit, Herning Regional Hospital, Herning, Denmark. Electronic address: mogmad@rm.dk.
authors.forename: Mogens R
authors.initials: MR
authors.lastname: Madsen
authors.affiliation: Department of Surgery, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: soerlaur@rm.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Laurberg
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: Sean.McGuire@bcm.edu.
authors.forename: Sean E
authors.initials: SE
authors.lastname: McGuire
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: orntoft@clin.au.dk.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. Electronic address: cla@clin.au.dk.
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D059372:Nucleotide Motifs / Q000235:genetics; D011132:Polyribosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D020537:RNA, Small Nucleolar / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D020537:RNA, Small Nucleolar; C000624322:SNHG16 lncRNA, human; D014157:Transcription Factors
keywords: AGO-CLIP; Colorectal cancer; Functional analyses; Long non-coding RNAs; SNHG16; Wnt pathway