A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells

Autor: Xiao-Ning Gao, Li-Li Wang, Ji Lin, Yonghui Li, Jihao Zhou, Yushi Yao, Qiaoyang Ning, Li Gao, Li Yu
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Myeloid
Oncogene Proteins
Fusion
Cancer Treatment
Gene Expression
lcsh:Medicine
Apoptosis
Biochemistry
Hematologic Cancers and Related Disorders
Histones
Mice
RUNX1 Translocation Partner 1 Protein
hemic and lymphatic diseases
Molecular Cell Biology
Granulocyte Colony-Stimulating Factor
p300-CBP Transcription Factors
Enzyme Inhibitors
lcsh:Science
Regulation of gene expression
Histone Acetyltransferase p300
Multidisciplinary
Gene Expression Regulation
Leukemic
Physics
Myeloid leukemia
Histone Modification
Acetylation
Hematology
Leukemia
Myeloid
Acute
Proto-Oncogene Proteins c-kit
Leukemia
medicine.anatomical_structure
Oncology
Proto-Oncogene Proteins c-bcl-2
Core Binding Factor Alpha 2 Subunit
Medicine
Epigenetics
Female
Cell Division
Research Article
Signal Transduction
Acute Myeloid Leukemia
Biophysics
Biology
Protein Chemistry
Cell Line
Tumor
Leukemias
Genetics
medicine
Animals
Humans
Histone H3 acetylation
Cell Proliferation
lcsh:R
Proteins
Cell Cycle Checkpoints
Chemotherapy and Drug Treatment
Hematopoietic Stem Cells
medicine.disease
Molecular biology
Mice
Inbred C57BL
Cell culture
lcsh:Q
Zdroj: PLoS ONE, Vol 8, Iss 2, p e55481 (2013)
PLoS ONE
ISSN: 1932-6203
Popis: AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.
Databáze: OpenAIRE
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