scholarly journals HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma

2019 ◽  
Author(s):  
Mariane da Cunha Jaeger ◽  
Eduarda Chiesa Ghisleni ◽  
Paula Schoproni Cardoso ◽  
Marialva Siniglaglia ◽  
Tiago Falcon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Hdac Inhibition ◽  
Single Drug ◽  
Mitogen Activated Protein ◽  
Drug Treatments ◽  
Erk Inhibition ◽  
Developing Cerebellum

AbstractMedulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markersBMI1andCD133are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression ofBMI1andCD133and increased acetylation in human MB cells. Enrichment analysis of genes associated withCD133orBMI1expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

scholarly journals p38 Mitogen-Activated Protein Kinase Activity Commits Embryonic Stem Cells to Either Neurogenesis or Cardiomyogenesis

Stem Cells ◽  
2006 ◽  
Vol 24 (5) ◽  
pp. 1399-1406 ◽  
Author(s):  
Myriam Aouadi ◽  
Frédéric Bost ◽  
Leslie Caron ◽  
Kathiane Laurent ◽  
Yannick Le Marchand Brustel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Embryonic Stem ◽  
Mitogen Activated Protein Kinase ◽  
Protein Kinase Activity ◽  
Mitogen Activated Protein

scholarly journals Thrombopoietin Induces HOXA9 Nuclear Transport in Immature Hematopoietic Cells: Potential Mechanism by Which the Hormone Favorably Affects Hematopoietic Stem Cells

2004 ◽  
Vol 24 (15) ◽  
pp. 6751-6762 ◽  
Author(s):  
Keita Kirito ◽  
Norma Fox ◽  
Kenneth Kaushansky
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Hematopoietic Stem Cells ◽  
Nuclear Translocation ◽  
Hematopoietic Cells ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Hematopoietic Stem ◽  
Nuclear Localization Signals ◽  
Mitogen Activated Protein

ABSTRACT Members of the homeobox family of transcription factors are major regulators of hematopoiesis. Overexpression of either HOXB4 or HOXA9 in primitive marrow cells enhances the expansion of hematopoietic stem cells (HSCs). However, little is known of how expression or function of these proteins is regulated during hematopoiesis under physiological conditions. In our previous studies we demonstrated that thrombopoietin (TPO) enhances levels of HOXB4 mRNA in primitive hematopoietic cells (K. Kirito, N. Fox, and K. Kaushansky, Blood 102:3172-3178, 2003). To extend our studies, we investigated the effects of TPO on HOXA9 in this same cell population. Although overall levels of the transcription factor were not affected, we found that TPO induced the nuclear import of HOXA9 both in UT-7/TPO cells and in primitive Sca-1+/c-kit+/Gr-1− hematopoietic cells in a mitogen-activated protein kinase-dependent fashion. TPO also controlled MEIS1 expression at mRNA levels, at least in part due to phosphatidylinositol 3-kinase activation. Collectively, TPO modulates the function of HOXA9 by leading to its nuclear translocation, likely mediated by effects on its partner protein MEIS1, and potentially due to two newly identified nuclear localization signals. Our data suggest that TPO controls HSC development through the regulation of multiple members of the Hox family of transcription factors through multiple mechanisms.

scholarly journals Histone Deacetylase Inhibitor Impairs Plasminogen Activator Inhibitor-1 Expression via Inhibiting TNF-α-Activated MAPK/AP-1 Signaling Cascade

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Wei-Lin Chen ◽  
Joen-Rong Sheu ◽  
Che-Jen Hsiao ◽  
Shih-Hsin Hsiao ◽  
Chi-Li Chung ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Histone Deacetylases ◽  
Plasminogen Activator Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Hdac Inhibition ◽  
Plasminogen Activator Inhibitor 1 ◽  
Hdac Activity ◽  
Mitogen Activated Protein ◽  
Activator Inhibitor ◽  
Pai 1

Tumor necrosis factor-(TNF-)-αupregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-αor HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-α-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-αin the presence or absence of them-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-α-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-α-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.

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