title: SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of "cancer cells with neural stemness" in a p53-dependent manner.
abstract: BACKGROUND
  Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo.
  
  
  METHODS
  We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type information regulation 2, homolog (SIRT1) as a key factor in maintaining cancer stemness.
  
  
  RESULTS
  We demonstrate that the expression of SIRT1, expressed in "cancer cells with neural stemness," is critical not only for the maintenance of stem cells, but also for oncogenic transformation. Interestingly, SIRT1 is essential for the survival and tumorigenicity of F3.Ras.CNSCs and GSCs but not for the U87 glioma cell line.
  
  
  CONCLUSIONS
  These results indicate that expression of SIRT1 in cancer cells with neural stemness plays an important role in suppressing p53-dependent tumor surveillance, the abrogation of which may be responsible not only for inducing oncogenic transformation but also for retaining the neural cancer stemness of the cells, suggesting that SIRT1 may be a putative therapeutic target in GSCs.
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Jeong-Rak
authors.initials: JR
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Ok-Seon
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Kwang-Hoon
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Hong Jun
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Sogang University, Seoul, Korea (J.-S.L., J.-R.P., O.-S.K., H.-J.C.); Laboratory of Cancer and Stem Cell Biology, Sejong University, Seoul, Korea (T.-H.L.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, (I.N.); Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, Wako, Japan (H.M.); Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Korea (K.-H.C.); Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (M.-J.P.); College of Medicine, Chung-Ang University, Seoul, Korea (H.J.L., S.U.K.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.J.L., S.U.K.).
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: H-Ras; SIRT1; glioma stem cells; human neural stem cell; p53
references.citation: Nat Biotechnol. 1998 Nov;16(11):1033-9
references.pmid: 9831031
references.citation: Stem Cells. 2013 May;31(5):870-81
references.pmid: 23339114
references.citation: Dev Neurosci. 2004 Mar-Aug;26(2-4):148-65
references.pmid: 15711057
references.citation: Oncogene. 2013 Oct;32(40):4737-47
references.pmid: 23146903
references.citation: Mol Cell. 2007 Oct 26;28(2):277-90
references.pmid: 17964266
references.citation: Biochem Biophys Res Commun. 2009 Mar 6;380(2):236-42
references.pmid: 19166820
references.citation: Br J Cancer. 2001 May 18;84(10):1372-6
references.pmid: 11355949
references.citation: Cancer Res. 2001 May 1;61(9):3556-60
references.pmid: 11325817
references.citation: Biochem Biophys Res Commun. 2009 Sep 4;386(4):671-5
references.pmid: 19555662
references.citation: Nat Rev Cancer. 2006 Jun;6(6):472-6
references.pmid: 16723993
references.citation: Oncogene. 2008 May 1;27(20):2801-9
references.pmid: 18193093
references.citation: Nat Cell Biol. 2008 Apr;10(4):385-94
references.pmid: 18344989
references.citation: Nature. 2009 Jan 29;457(7229):608-11
references.pmid: 19092804
references.citation: Neurosci Lett. 2012 Sep 13;525(2):168-72
references.pmid: 22867969
references.citation: J Neurosci Res. 2011 Nov;89(11):1723-36
references.pmid: 21826702
references.citation: PLoS One. 2013;8(3):e59890
references.pmid: 23533656
references.citation: Cell. 2001 Oct 19;107(2):149-59
references.pmid: 11672523
references.citation: Cell. 2001 Oct 19;107(2):137-48
references.pmid: 11672522
references.citation: EMBO J. 2009 Mar 18;28(6):663-76
references.pmid: 19214186
references.citation: Nature. 2009 Aug 27;460(7259):1132-5
references.pmid: 19668191
references.citation: Cell. 2008 May 16;133(4):612-26
references.pmid: 18485870
references.citation: Mol Cancer Ther. 2010 Apr;9(4):844-55
references.pmid: 20371709
references.citation: Cancer Cell. 2012 Feb 14;21(2):266-81
references.pmid: 22340598
references.citation: J Biol Chem. 2011 Feb 11;286(6):4264-70
references.pmid: 21148320
references.citation: Front Biosci (Landmark Ed). 2012 Jan 01;17:1480-98
references.pmid: 22201816
references.citation: Cancer Res. 2007 May 1;67(9):4010-5
references.pmid: 17483311
references.citation: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8644-9
references.pmid: 23650391
references.citation: Exp Gerontol. 2000 May;35(3):317-29
references.pmid: 10832053
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Mol Cell. 2006 Dec 28;24(6):841-51
references.pmid: 17189187
references.citation: Stem Cell Rev Rep. 2012 Jun;8(2):532-45
references.pmid: 21755312
references.citation: J Biol Chem. 2014 Feb 21;289(8):5208-16
references.pmid: 24379401
references.citation: Aging Cell. 2006 Feb;5(1):81-8
references.pmid: 16441846
references.citation: Mol Cancer. 2006 Dec 02;5:67
references.pmid: 17140455
references.citation: Stem Cells. 2013 Jun;31(6):1051-63
references.pmid: 23404835
references.citation: Cancer Res. 2012 Nov 15;72(22):6065-75
references.pmid: 22986743
references.citation: Int J Biol Sci. 2009;5(2):147-52
references.pmid: 19173036
references.citation: Oncogene. 2002 Oct 7;21(45):6908-14
references.pmid: 12362273
references.citation: J Biol Chem. 2009 Apr 24;284(17):11171-83
references.pmid: 19265193
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15599-604
references.pmid: 18829436