scholarly journals Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis

Oncotarget ◽  
2016 ◽  
Vol 8 (6) ◽  
pp. 9647-9659 ◽  
Author(s):  
Katarina Lyberg ◽  
Hani Abdulkadir Ali ◽  
Jennine Grootens ◽  
Matilda Kjellander ◽  
Malin Tirfing ◽  
...  
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Systemic Mastocytosis ◽  
Epigenetic Silencing ◽  
Deacetylase Inhibitor ◽  
Constitutively Active

Histone Deacetylase Inhibitor SAHA Mediates Epigenetic Silencing of KIT D816V Mutated Systemic Mastocytosis Primary Mast Cells and Selective Apoptosis of Mutated Mast Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2834-2834 ◽  
Author(s):  
Hani Abdulkadir ◽  
Jennine Grootens ◽  
Matilda Kjellander ◽  
Eva Hellstrom Lindberg ◽  
Gunnar Nilsson ◽  
...  
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
Mast Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Specific Treatment ◽  
Epigenetic Silencing ◽  
Kit Receptor

Abstract Systemic mastocytosis (SM) is a myeloproliferative disease for which there is currently no specific therapy. Over 90% of the patients carry the D816V point mutation that renders the KIT receptor constitutively active. In the current study, we assessed the sensitivity of mast cell line HMC1.2 and primary SM patient mast cells to histone deacetylase inhibitors, and found that SAHA is most efficient. SAHA induced a rapid downregulation of KIT mRNA, with a subsequent reduction in total KIT protein as well as cell surface KIT. This was followed by major mast cell apoptosis. Primary SM patient mast cells cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas healthy subject mast cells were unaffected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive disease, with almost 100% cell death among mast cells from the mast cell leukemia patient. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/totalH3 decreased significantly in the KIT region, due to an increase in H3 density. This epigenetic silencing was specific to the KIT region and not seen in control genes upstream and downstream of KIT. Primary analysis of ChIP-seq data for histone marks H3K4me3 and H3K27me3, demonstrates a downregulation of transcription factors involved in activation of KIT receptor, such as MAPK, for the SAHA treated samples. This indicates an indirect epigenetic silencing of KIT. Our results therefore demonstrate that SAHA epigenetically silences KIT, and work is ongoing to elucidate the exact mechanisms of KIT regulation. Altogether, SAHA maybe a specific treatment for SM. Disclosures No relevant conflicts of interest to declare.

A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways

2009 ◽  
Vol 20 (9) ◽  
pp. 815-821 ◽  
Author(s):  
Jung Jin Hwang ◽  
Yong Sook Kim ◽  
Mi Joung Kim ◽  
Sejin Jang ◽  
Je-Hwan Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Deacetylase Inhibitor ◽  
Intrinsic Apoptotic Pathways ◽  
Apoptotic Pathways

Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells

2010 ◽  
Vol 30 (2) ◽  
pp. 435-442 ◽  
Author(s):  
Eun-Taex Oh ◽  
Moon-Taek Park ◽  
Bo-Hwa Choi ◽  
Seonggu Ro ◽  
Eun-Kyung Choi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Deacetylase Inhibitor ◽  
Clonogenic Cell

scholarly journals CREB-Binding Protein Is a Mediator of Neuroblastoma Cell Death Induced By the Histone Deacetylase Inhibitor Trichostatin A

Neoplasia ◽  
2007 ◽  
Vol 9 (6) ◽  
pp. 495-503 ◽  
Author(s):  
Chitra Subramanian ◽  
Jason A. Jarzembowski ◽  
Anthony W. Opipari ◽  
Valerie P. Castle ◽  
Roland P.S. Kwok
Keyword(s):  
Cell Death ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Binding Protein ◽  
Trichostatin A ◽  
Neuroblastoma Cell ◽  
Creb Binding Protein ◽  
Deacetylase Inhibitor ◽  
Histone Deacetylase Inhibitor Trichostatin
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