Natural HDAC‐1/8 inhibitor baicalein exerts therapeutic effect in CBF‐AML. Issue 4 (26th August 2020)

• Record Type: Journal Article
• Authors: Yu, Xiaoxuan; Li, Hui; Hu, Po; Qing, Yingjie; Wang, Xiangyuan; Zhu, Mengyuan; Wang, Hongzheng; Wang, Zhanyu; Xu, Jingyan; Guo, Qinglong; Hui, Hui
• Is Part Of: Clinical and translational medicine. Volume 10:Issue 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-08-26
• Subjects: ABC transporter genes -- CBF‐AML -- differentiation -- HDAC‐1/8 inhibitors -- natural product; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.154
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: Background: Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor‐acute myeloid leukemia (CBF‐AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug‐resistant characteristic. Our purpose is to evaluate the anti‐leukemia effects of Baicalein on CBF‐AML and clarify its underlying mechanism. Methods: Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT‐qPCR were employed to evaluate the distribution of drugs and the change of ATP‐binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC‐1 and ubiquitin, HSP90 and AML1‐ETO, and Ac‐p53 and CBFβ‐MYH11. AML cell lines and primary AML cells‐bearing NOD/SCID mice models were used to evaluate the anti‐leukemic efficiency and potential mechanism of Baicalein in vivo. Results: Baicalein showed HDAC‐1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC‐1 was mild, Baicalein could induce the degradation of HDAC‐1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1‐ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53‐mediated apoptosis genes expression. Moreover, CBFβ‐MYH11‐bound p53 acetylation was restored via HDAC‐8 inhibition induced by Baicalein contributing the diminishing of survival of CD34 + inv(16) AML cells. Conclusions: These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF‐AML. Abstract : Baicalein shows HDAC1/8 inhibition without promoting ABC transporter genes expression.2. Baicalein exerts therapeutic effect in CBF‐AML.3. The inhibition of HDAC1/8 could be potential therapeutic target for CBF‐AML treatment.