The histone methyltransferase inhibitor A-366 enhances hemoglobin expression in erythroleukemia cells upon co‐exposure with chemical inducers in culture

Autor: Nikoleta F Theodoroula, Ioannis S. Vizirianakis, Nikolaos Grigoriadis, Konstantina Tsouderou, Maria Kosmidou, Christos I Papagiannopoulos, Melpomeni G. Akrivou, Konstantinos Kyritsis
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Biological Research-Thessaloniki, Vol 28, Iss 1, Pp 1-14 (2021)
Journal of Biological Research
ISSN: 2241-5793
Popis: Background Erythroleukemia is caused by the uncontrolled multiplication of immature erythroid progenitor cells which fail to differentiate into erythrocytes. By directly targeting this class of malignant cells, the induction of terminal erythroid differentiation represents a vital therapeutic strategy for this disease. Erythroid differentiation involves the execution of a well-orchestrated gene expression program in which epigenetic enzymes play critical roles. In order to identify novel epigenetic mediators of differentiation, this study explores the effects of multiple, highly specific, epigenetic enzyme inhibitors, in murine and human erythroleukemia cell lines. Results We used a group of compounds designed to uniquely target the following epigenetic enzymes: G9a/GLP, EZH1/2, SMYD2, PRMT3, WDR5, SETD7, SUV420H1 and DOT1L. The majority of the probes had a negative impact on both cell proliferation and differentiation. On the contrary, one of the compounds, A-366, demonstrated the opposite effect by promoting erythroid differentiation of both cell models. A-366 is a selective inhibitor of the G9a methyltransferase and the chromatin reader Spindlin1. Investigation of the molecular mechanism of action revealed that A-366 forced cells to exit from the cell cycle, a fact that favored erythroid differentiation. Further analysis led to the identification of a group of genes that mediate the A-366 effects and include CDK2, CDK4 and CDK6. Conclusions A-366, a selective inhibitor of G9a and Spindlin1, demonstrates a compelling role in the erythroid maturation process by promoting differentiation, a fact that is highly beneficial for patients suffering from erythroleukemia. In conclusion, this data calls for further investigation towards the delivery of epigenetic drugs and especially A-366 in hematopoietic disorders.
Databáze: OpenAIRE
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