title: p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.
abstract: The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: Institute of Pathology, University of Medicine, Greifswald 17487, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Institute of Pathology, University of Medicine, Greifswald 17487, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Michurina
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Banito
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm 89070, Germany.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Katz
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Susann
authors.initials: S
authors.lastname: Weissmueller
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm 89070, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Laboratory of Experimental Carcinogenesis, NCI/CCR, NIH, Bethesda, MD 20892, USA; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Institute of Pathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D064231:Nestin / Q000378:metabolism*; D011379:Prognosis; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C577484:NES protein, human; D064231:Nestin; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051705:Sp3 Transcription Factor
references.citation: Cell Death Differ. 2003 Apr;10(4):404-8
references.pmid: 12719716
references.citation: Nature. 2009 Aug 27;460(7259):1140-4
references.pmid: 19668186
references.citation: Oncogene. 2006 Jun 26;25(27):3818-22
references.pmid: 16799623
references.citation: Hepatology. 2012 Nov;56(5):1817-27
references.pmid: 22689435
references.citation: Cell. 2013 Apr 11;153(2):449-60
references.pmid: 23562644
references.citation: Nature. 2013 Nov 14;503(7475):218-23
references.pmid: 24196716
references.citation: J Clin Invest. 2012 Aug;122(8):2911-5
references.pmid: 22797301
references.citation: Science. 2012 Nov 23;338(6110):1080-4
references.pmid: 23087000
references.citation: Nature. 2012 Aug 23;488(7412):522-6
references.pmid: 22854781
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19513-8
references.pmid: 24154728
references.citation: Nature. 2009 Aug 27;460(7259):1149-53
references.pmid: 19668189
references.citation: Oncogene. 2007 Apr 2;26(15):2166-76
references.pmid: 17401425
references.citation: Cancer Res. 2000 Jul 1;60(13):3655-61
references.pmid: 10910082
references.citation: Nat Med. 2012 Mar 04;18(4):572-9
references.pmid: 22388089
references.citation: Nat Med. 1996 Jul;2(7):804-10
references.pmid: 8673928
references.citation: Int J Cancer. 2011 Jan 15;128(2):343-51
references.pmid: 20669222
references.citation: Neoplasma. 2010;57(4):291-8
references.pmid: 20429619
references.citation: Genes Cancer. 2011 Apr;2(4):404-19
references.pmid: 21779509
references.citation: Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83
references.pmid: 17380161
references.citation: Cell. 2004 Nov 24;119(5):591-602
references.pmid: 15550242
references.citation: Nat Genet. 2000 May;25(1):35-41
references.pmid: 10802653
references.citation: Semin Liver Dis. 2011 May;31(2):173-87
references.pmid: 21538283
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22745-50
references.pmid: 21149740
references.citation: Trends Cell Biol. 2011 Apr;21(4):212-8
references.pmid: 21236679
references.citation: Nature. 2009 Aug 27;460(7259):1132-5
references.pmid: 19668191
references.citation: Cell. 2009 May 1;137(3):413-31
references.pmid: 19410540
references.citation: Hepatology. 2009 May;49(5):1655-63
references.pmid: 19309719
references.citation: Cell Res. 2006 Mar;16(3):319-22
references.pmid: 16541131
references.citation: Nature. 2009 Dec 3;462(7273):595-601
references.pmid: 19898493
references.citation: EMBO J. 2006 Oct 18;25(20):4808-19
references.pmid: 17036052
references.citation: Dev Dyn. 2005 Oct;234(2):413-21
references.pmid: 16127706
references.citation: Cell. 2007 Sep 21;130(6):1120-33
references.pmid: 17889654
references.citation: Blood. 1994 Apr 15;83(8):2230-7
references.pmid: 8161788
references.citation: Carcinogenesis. 2010 Aug;31(8):1311-8
references.pmid: 20097732
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21276-81
references.pmid: 22123976
references.citation: J Comp Neurol. 2004 Feb 9;469(3):311-24
references.pmid: 14730584
references.citation: Mol Carcinog. 1994 Feb;9(2):71-5
references.pmid: 8142011
references.citation: Oncol Rep. 2013 Oct;30(4):1782-92
references.pmid: 23877322
references.citation: Gastroenterology. 2012 May;142(5):1229-1239.e3
references.pmid: 22342966
references.citation: Genes Dev. 1991 Dec;5(12B):2375-85
references.pmid: 1752433
references.citation: J Clin Invest. 2012 Nov;122(11):3914-8
references.pmid: 23023701
references.citation: Cell. 2000 Aug 18;102(4):407-10
references.pmid: 10966103
references.citation: Lung Cancer. 2013 Aug;81(2):174-9
references.pmid: 23706418
references.citation: Cell. 2013 Jan 17;152(1-2):25-38
references.pmid: 23273993
references.citation: Nat Protoc. 2007;2(12):3153-65
references.pmid: 18079715
references.citation: Cell Cycle. 2008 Sep 15;7(18):2856-67
references.pmid: 18769160
references.citation: Cell. 2011 May 13;145(4):571-83
references.pmid: 21565614
references.citation: Nature. 2007 Feb 8;445(7128):656-60
references.pmid: 17251933
references.citation: Cell. 2006 Jun 30;125(7):1253-67
references.pmid: 16814713
references.citation: Gastroenterology. 2012 Apr;142(4):1021-1031.e15
references.pmid: 22178589
references.citation: Liver Int. 2012 Jan;32(1):38-47
references.pmid: 22098159
references.citation: Cell. 2008 Jul 11;134(1):62-73
references.pmid: 18614011
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17392-7
references.pmid: 24101460
references.citation: Nat Cell Biol. 2005 Feb;7(2):165-71
references.pmid: 15619621
references.citation: Nature. 2006 May 25;441(7092):537-41
references.pmid: 16724069
references.citation: FEBS Lett. 2004 May 7;565(1-3):195-202
references.pmid: 15135078