PUBLICATION
Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia
- Authors
- Zhou, B., Li, H., Xing, C., Ye, H., Feng, J., Wu, J., Lu, Z., Fang, J., Gao, S.
- ID
- ZDB-PUB-170104-4
- Date
- 2017
- Source
- Biochemical pharmacology 128: 12-25 (Journal)
- Registered Authors
- Keywords
- AML1-ETO, Honokiol, Honokiol (PubChem CID 72303), UbcH8, trichostatin A (PubChem CID 444732)
- MeSH Terms
-
- Acetylation
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology*
- Apoptosis
- Biphenyl Compounds/pharmacology*
- Cell Line, Tumor
- Core Binding Factor Alpha 2 Subunit/metabolism*
- Embryo, Nonmammalian/blood supply
- Embryo, Nonmammalian/drug effects
- Humans
- Leukemia, Myeloid, Acute/drug therapy*
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Lignans/pharmacology*
- Male
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Neovascularization, Physiologic/drug effects
- Oncogene Proteins, Fusion/metabolism*
- Promoter Regions, Genetic
- Proteasome Endopeptidase Complex/metabolism*
- Ubiquitin-Conjugating Enzymes/genetics
- Ubiquitin-Conjugating Enzymes/metabolism*
- Zebrafish
- PubMed
- 28043811 Full text @ Biochem. Pharmacol.
Citation
Zhou, B., Li, H., Xing, C., Ye, H., Feng, J., Wu, J., Lu, Z., Fang, J., Gao, S. (2017) Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia. Biochemical pharmacology. 128:12-25.
Abstract
AML1-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AML1-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration-and time-dependent manner in leukemic cell lines and primary AML blasts with t(8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AML1-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AML1-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping