Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.

Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia. Biochem Pharmacol. 2016 Dec 30;: Authors: Zhou B, Li H, Xing C, Ye H, Feng J, Wu J, Lu Z, Fang J, Gao S 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 zebra...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research