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MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells

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 c...

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Autores principales: Joshi, Kaushal, Banasavadi-Siddegowda, Yeshavanth, Mo, Xiaokui, Kim, Sung-Hak, Mao, Ping, Kig, Cenk, Nardini, Diana, Sobol, Robert W, Chow, Lionel ML, Kornblum, Harley I, Waclaw, Ronald, Beullens, Monique, Nakano, Ichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wiley Subscription Services, Inc., A Wiley Company 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744761/
https://www.ncbi.nlm.nih.gov/pubmed/23404835
http://dx.doi.org/10.1002/stem.1358
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author Joshi, Kaushal
Banasavadi-Siddegowda, Yeshavanth
Mo, Xiaokui
Kim, Sung-Hak
Mao, Ping
Kig, Cenk
Nardini, Diana
Sobol, Robert W
Chow, Lionel ML
Kornblum, Harley I
Waclaw, Ronald
Beullens, Monique
Nakano, Ichiro
author_facet Joshi, Kaushal
Banasavadi-Siddegowda, Yeshavanth
Mo, Xiaokui
Kim, Sung-Hak
Mao, Ping
Kig, Cenk
Nardini, Diana
Sobol, Robert W
Chow, Lionel ML
Kornblum, Harley I
Waclaw, Ronald
Beullens, Monique
Nakano, Ichiro
author_sort Joshi, Kaushal
collection PubMed
description 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. Stem Cells 2013;31:1051–1063
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spelling pubmed-37447612013-08-16 MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells Joshi, Kaushal Banasavadi-Siddegowda, Yeshavanth Mo, Xiaokui Kim, Sung-Hak Mao, Ping Kig, Cenk Nardini, Diana Sobol, Robert W Chow, Lionel ML Kornblum, Harley I Waclaw, Ronald Beullens, Monique Nakano, Ichiro Stem Cells Cancer Stem Cells 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. Stem Cells 2013;31:1051–1063 Wiley Subscription Services, Inc., A Wiley Company 2013-06 2013-02-13 /pmc/articles/PMC3744761/ /pubmed/23404835 http://dx.doi.org/10.1002/stem.1358 Text en Copyright © 2013 AlphaMed Press http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Cancer Stem Cells
Joshi, Kaushal
Banasavadi-Siddegowda, Yeshavanth
Mo, Xiaokui
Kim, Sung-Hak
Mao, Ping
Kig, Cenk
Nardini, Diana
Sobol, Robert W
Chow, Lionel ML
Kornblum, Harley I
Waclaw, Ronald
Beullens, Monique
Nakano, Ichiro
MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title_full MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title_fullStr MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title_full_unstemmed MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title_short MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells
title_sort melk-dependent foxm1 phosphorylation is essential for proliferation of glioma stem cells
topic Cancer Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744761/
https://www.ncbi.nlm.nih.gov/pubmed/23404835
http://dx.doi.org/10.1002/stem.1358
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