title: MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells.
abstract: Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator of mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the mitotic kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. This MELK-dependent activation of FOXM1 results in a subsequent increase in mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1. Using mouse neural progenitor cells (NPCs), we found that transgenic expression of FOXM1 enhances, while siRNA-mediated gene silencing diminishes neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases as cells progress from NPCs, to pretumorigenic progenitors and GSCs. The antibiotic Siomycin A disrupts MELK-mediated FOXM1 signaling with a greater sensitivity in GSC compared to neural stem cell. Treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cells, and addition of Siomycin A to Temozolomide treatment in mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with MELK regulates key mitotic genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM.
authors: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Kaushal
authors: K
authors: Joshi
authors: Yeshavanth
authors: Y
authors: Banasavadi-Siddegowda
authors: Xiaokui
authors: X
authors: Mo
authors: Sung-Hak
authors: SH
authors: Kim
authors: Ping
authors: P
authors: Mao
authors: Cenk
authors: C
authors: Kig
authors: Diana
authors: D
authors: Nardini
authors: Robert W
authors: RW
authors: Sobol
authors: Lionel M L
authors: LM
authors: Chow
authors: Harley I
authors: HI
authors: Kornblum
authors: Ronald
authors: R
authors: Waclaw
authors: Monique
authors: M
authors: Beullens
authors: Ichiro
authors: I
authors: Nakano
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D015854:Up-Regulation / Q000187:drug effects; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D003606:Dacarbazine; D051858:Forkhead Transcription Factors; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1; C024711:siomycin A
references: Nature. 2006 Dec 7;444(7120):756-60
references: 17051156
references: J Vis Exp. 2011 Jul 29;(53):
references: 21841761
references: Mol Cell Biol. 2005 Dec;25(24):10875-94
references: 16314512
references: Expert Rev Anticancer Ther. 2006 Jul;6(7):1087-104
references: 16831080
references: Clin Cancer Res. 2013 Feb 1;19(3):631-42
references: 23251006
references: Cancer Res. 2006 Oct 1;66(19):9731-5
references: 17018632
references: Pharm Res. 2010 Jun;27(6):1159-68
references: 20354770
references: Chin Med J (Engl). 2009 Jun 5;122(11):1255-9
references: 19567133
references: Biochim Biophys Acta. 2007 Jan;1775(1):92-102
references: 17014965
references: Nature. 2012 Aug 23;488(7412):522-6
references: 22854781
references: J Cell Biol. 2005 Aug 1;170(3):413-27
references: 16061694
references: Stem Cells. 2013 May;31(5):870-81
references: 23339114
references: Cancer Res. 2005 Jun 15;65(12):5181-9
references: 15958562
references: Mol Cancer Res. 2009 Jul;7(7):989-99
references: 19609002
references: Cancer Cell. 2011 Oct 18;20(4):427-42
references: 22014570
references: Nat Cell Biol. 2008 Sep;10(9):1076-82
references: 19160488
references: Cancer Cell. 2008 Jan;13(1):3-4
references: 18167333
references: Cancer Res. 2006 Apr 1;66(7):3593-602
references: 16585184
references: Mech Dev. 1996 Jun;57(1):3-20
references: 8817449
references: Nat Cell Biol. 1999 Nov;1(7):438-43
references: 10559988
references: Cancer Res. 2008 Nov 1;68(21):8733-42
references: 18974115
references: Cancer Res. 2003 Sep 15;63(18):5821-8
references: 14522905
references: Cell. 2007 Sep 21;130(6):1160
references: 17889656
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: Cancer Res. 2008 May 1;68(9):3286-94
references: 18451155
references: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
references: 17090670
references: PLoS One. 2009;4(5):e5592
references: 19440351
references: Biochem Pharmacol. 2010 Sep 1;80(5):654-65
references: 20457135
references: Clin Cancer Res. 2012 Mar 1;18(5):1268-80
references: 22230766
references: Cancer Res. 2010 Nov 15;70(22):9243-52
references: 20935218
references: Neuro Oncol. 2011 Jun;13(6):622-34
references: 21558073
references: J Neurooncol. 2011 Sep;104(2):509-22
references: 21336775
references: Cancer Cell. 2011 Nov 15;20(5):620-34
references: 22094256
references: Ann Neurol. 2012 Nov;72(5):766-78
references: 23280793
references: Mol Cancer. 2011 Oct 11;10:128
references: 21988793
references: Genes Dev. 2004 Apr 1;18(7):830-50
references: 15082532
references: PLoS One. 2011;6(9):e24217
references: 21915300
references: Nature. 2008 Oct 23;455(7216):1061-8
references: 18772890
references: Cell. 2007 Oct 5;131(1):192
references: 17923097
references: Carcinogenesis. 2010 Nov;31(11):2012-21
references: 20823107
references: Cancer Cell. 2006 Mar;9(3):157-73
references: 16530701
references: Cancer Res. 2010 Nov 1;70(21):8863-73
references: 20861186
references: Cancer Res. 2002 Aug 15;62(16):4773-80
references: 12183437
references: Cancer Res. 2010 Jan 15;70(2):453-62
references: 20068170
references: J Cell Sci. 2011 Mar 15;124(Pt 6):958-68
references: 21378312
references: Stem Cells. 2012 May;30(5):833-44
references: 22489015
references: J Neurosci Res. 2008 Jan;86(1):48-60
references: 17722061
references: J Biol Chem. 2005 Dec 2;280(48):40003-11
references: 16216881