title: Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.
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.
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Chongyun
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Haige
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Feng
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang Province 325000, China. Electronic address: 782917063@qq.com.
authors.forename: Shenmeng
authors.initials: S
authors.lastname: Gao
mesh_terms: D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D050676:Core Binding Factor Alpha 2 Subunit; D017705:Lignans; D015514:Oncogene Proteins, Fusion; D046988:Proteasome Endopeptidase Complex; D000075142:RUNX1 Translocation Partner 1 Protein; D044763:Ubiquitin-Conjugating Enzymes; C107844:AML1-ETO fusion protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C471622:UBE2L6 protein, human
keywords: AML1-ETO; Honokiol; Honokiol (PubChem CID 72303); Trichostatin A (PubChem CID 444732); UbcH8